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High quality evidence of the effects of medicines in people with mitochondrial disease is sparse. Much of the available information is derived from in vitro or animal studies. Additionally, due to the great diversity in mitochondrial disease manifestations, conflicting outcomes can be reported in different patients for the same medicine.
Consensus appears to be lacking on which medicines should be completely avoided and which may be used with close monitoring 1—5. A summary of the available data is provided in Table 1.
Key Messages Medicines can affect a variety of mitochondrial functions. Medicines that are toxic to mitochondrial functions should be avoided in patients with mitochondrial disorders. Due to the great diversity in mitochondrial disease manifestations differing outcomes can be reported in different patients for the same medicine. Mitochondrial diseases are remarkably heterogeneous. Clinically distinct mitochondrial disease syndromes such as Leigh syndrome and MELAS differ from each other age of onset, organ system involvement, and specific disease sequelae, but disease course and individual symptoms can differ greatly even among patients with the same diagnosed disorder or causal mutation.
Multi-system mitochondrial disorders are most defined by neurologic, metabolic, and muscular symptoms, but mitochondrial defects can impact every organ system, including the immune system. Altered immune system function is a well-documented possible sequalae of genetic mitochondrial dysfunction, but available data indicate that the nature of immune system involvement is extremely complex and very poorly understood.
Recent data, detailed below, clearly demonstrate that aberrant immune activation plays a key causal role in the pathogenesis of some forms of genetic mitochondrial disease discussed below. However, reduced or impaired immune function is a source of acute medical distress in mitochondrial disease, and infections are a major cause of morbidity and mortality in these patients; many experience recurrent infections and delayed recovery following infection, and in some studies sepsis and pneumonia are the most common proximal causes of death [ 21 , 22 , 23 , 24 ].
Many mitochondrial disease patients are evaluated for immune deficiency during the diagnosis process. These striking data not only raise clinically and scientifically significant questions about the nature of immune system defects in mitochondrial disease, but also highlight how much we do not yet know about these disorders.
In addition to reports associating mitochondrial disease in toto with immune dysfunction, some individual mitochondrial diseases are clearly associated with specific immune defects. Low white blood cell counts leukopenia have been reported in multiple forms of mitochondrial disease.
Cytochrome C oxidase COX activity has been shown to influence T-cell functions in a sub-population dependent manner and lead to immune deficiency, while COX defects in mice impair B-cell positive selection [ 29 , 30 ]. Also in mice, mitochondrial CIII function has been shown to be important for antigen-specific T-cell activation and invariant NK cell development and function [ 31 , 32 ].
Our aim here is to summarize evidence linking immune activity to disease pathogenesis in genetic mitochondrial disease, so a full review of immunometabolism and the role of mitochondria in immune system function is beyond our scope; many high-quality literature reviews expand on these topics for some examples, see [ 33 , 34 , 35 , 36 ].
An array of evidence from case reports and natural history studies suggests immune involvement in the pathogenesis of genetic mitochondrial diseases see Fig. Clinical evidence of immune-mediated disease pathogenesis in the setting of genetic mitochondrial disease. In LHON, progressive damage and functional compromise of the optic nerve results in vision loss. Vascular abnormalities and swelling can be detected early in disease.
Though direct evidence for immune involvement in humans is sparse, some data suggests that early-stage LHON is responsive to corticosteroids [ 37 , 38 ].
MS has been causally linked to inflammation, while evidence increasingly supports a role for mitochondrial dysfunction [ 41 , 42 , 43 ]. Mitochondrial disease arising from defects in mitochondrial apoptosis inducing factor 1 AIFM1 can cause a wide range of symptoms including encephalomyopathy, cerebellar ataxia, peripheral neuropathy, etc. Clinical evidence for immune involvement is minimal see pre-clinical section below , but a patient with particularly severe disease presented with follicular bronchiolitis, a rare non-neoplastic B-cell hyperplasia typically associated with genetic immune defects, acquired immunodeficiencies, or autoimmune disease [ 44 , 52 ].
In Barth syndrome, while patients experience recurrent bacterial infections due to neutropenia, they also have persistently elevated plasma levels of the inflammatory cytokine interleukin 6 IL-6 , consistent with chronic inflammation, which are thought to contribute to muscle-wasting [ 53 , 54 , 55 ]. Mitochondrial leukoencephalopathy are mitochondrial disorders with CNS white matter involvement.
MRI of the brains of patients with these disorders reveal white matter pathology including contrast enhancement and diffusion restriction consistent with blood brain barrier breakdown and neuroinflammation [ 56 ].
Reactive microgliosis was also observed by histology in a subset of patients, though there was no evidence of peripheral immune cells in the CSF. Evidence for chronic inflammation has also been reported in patients with mutations in POLG1 encoding a subunit of the mtDNA polymerase : two case reports found oligoclonal banding in CSF versus plasma consistent with CSF autoimmunity and typically seen in multiple sclerosis, where a causal role for immune involvement is well accepted [ 57 , 58 , 59 , 60 , 61 ].
Transcriptomic analysis of muscle biopsies from TK2 deficiency patients has revealed increased expression of genes associated with inflammation [ 64 ]. Inflammation appears to play a role in the pathogenesis of the mitochondria-associated iron accumulation disease Friedreich ataxia FRDA. In addition to its use in treating immunoglobulin deficiencies, intravenous immunoglobulin IVIG therapy is a well-documented immune-suppressing therapeutic strategy used in autoimmune disorders such as systemic lupus erythematosus, antiphospholipid syndrome, Kawasaki disease, demyelinating diseases, autoimmune neuromuscular disease, and scleroderma [ 69 , 70 ].
In mitochondrial disease, a patient with a confirmed mitochondrial myopathy was found to have muscle T-cell infiltration upon biopsy and showed significant clinical improvement after IVIG therapy [ 71 ].
In another case report, three children with genetically and clinically distinct forms of mitochondrial disease were treated with immune targeting therapies. One responded well to corticosteroids alone, another stabilized with corticosteroids and the B-cell depleting drug rituximab, another failed to respond to corticosteroids but showed marked improvement following IVIG [ 72 ].
Perhaps most dramatically, an adult-onset Leigh syndrome patient was given plasmapheresis to treat a suspected autoimmune disease and experienced resolution of symptoms prior to the confirmation of a Leigh syndrome diagnosis, with a known causal homoplasmic ATP6A mtDNA variant and characteristic CNS lesions [ 73 ]. Strikingly, the patient remitted following therapy, but with IVIG once again showed substantial improvements in symptoms.
The authors concluded simply that the mechanism of benefit was unknown, but that ATP6A Leigh syndrome may involve underlying autoimmune mechanisms. Corticosteroids, as mentioned above, also appear to provide significant, and at times persistent, benefits in genetically and clinically distinct forms of mitochondrial disease [ 74 ].
These include MELAS [ 75 , 76 , 77 , 78 , 79 ], mitochondrial neurogastrointestinal encephalopathy MNGIE [ 80 ], mitochondrial myopathy [ 81 ], mitochondrial encephalomyopathy [ 82 , 83 ], mitochondrial leukoencephalopathy [ 56 ], and other forms of mitochondrial disease [ 84 , 85 , 86 ]. The clinical reversal of disease was so striking in some cases, as in the full reversal of CNS symptoms in MELAS with subsequent dependency on corticosteroids to prevent relapse, that authors suggested corticosteroids should be standard treatments in mitochondrial disease [ 76 ].
However, while corticosteroids may benefit many forms of mitochondrial disease, a review of case reports found that they are likely detrimental in one form of mitochondrial disease, Kearns-Sayre syndrome [ 74 ]. Whether a different immune targeting approach would yield benefits, or immune involvement is not universal in mitochondrial disease, remains to be determined.
In response to preclinical data from the Ndufs4 KO mouse detailed below , mechanistic target of rapamycin mTOR inhibitors have also recently been tested in small cohorts of mitochondrial disease patients. A recent trial reported the use of everolimus in two pediatric mitochondrial disease patients reported mixed responses [ 87 ]. A 2 year-old Leigh syndrome patient homozygous for the known pathogenic c.
In a separate study four post-transplant MELAS patients in terminal decline were transitioned from calcineurin inhibitors to mTOR inhibitors, and all four showed substantial improvement in over the following months [ 88 ].
While the answer to these questions is complex, immune functions appear to be one potent contributor to both onset and severity of genetic mitochondrial disease. Mitochondrial disease can present prenatally or at birth, but in many patients, symptoms do not appear until later. Adult-onset mitochondrial disease is well-documented, even in classically pediatric syndromes such as LS. Even in those with pediatric onset it is notable that symptoms are frequently absent at birth in many forms of mitochondrial disease.
Disease onset can vary widely both when comparing different clinically defined mitochondrial disease syndromes, as with the generally adult-onset MELAS versus typically pediatric onset Leigh syndrome, but also occur between patients with the same clinical disorder. It is hard to reconcile any post-natal onset of serious multi-system degenerative disorders such as LS, particularly in cases of adult-onset disease, with models where mitochondrial bioenergetics or ROS directly drive disease pathobiology.
While a robust link has not yet been established, viral infection and fever have been reported to coincide with symptom onset in mitochondrial disease [ 21 , 90 , 91 , 92 , 93 , 94 , 95 ]. For example, in three unrelated patients with POLG mutations, symptom onset followed infection with human herpesvirus 6 or Borrelia [ 96 , 97 ].
These patients all presented with severe seizures and rapid progressive neurodegeneration despite antivirals and antibiotics treatment and were eventually diagnosed with mitochondrial disease caused by POLG.
Borrelia infection has also been associated with the onset of disease in a case of LHON [ 98 ]. It has been hypothesized that this link is due to the energetic stress associated with induction of an immune response [ 91 ]. In light of the evidence for an immunologic origin of disease in LS it seems reasonable that it is the upregulated immune responses themselves that trigger disease onset.
Testing this possibility will require careful study using animal models. Similarly, while genetic mitochondrial diseases are progressive, the progression of symptoms is not linear—patients experience periods of relative stability interrupted by periods of deterioration. Reasons for ebbs and flow in disease are likely complex, but infections are one important factor. Moreover, there was a temporal delay of about a week between infection and neurodegenerative event—a timeframe the authors note is similar to that observed in Reye syndrome and suggest could be related to the induction of inflammatory cytokines or cellular mediators of immunity.
These findings are notable in light of recent findings linking mitochondrial function to T-cells immune regulatory function in mice discussed below. Finally, it appears possible that some mitochondrial defects only present when uncovered by an immunologic insult.
In at least one case, mitochondrial leukoencephalopathy which may have been precipitated by infection appeared reversible after recovery from acute illness—an infant with a DARS2 mutation experienced dramatic neurological deterioration after a respiratory tract infection at 9 months of age but gradually improved several months after resolution of the infection until nearly complete recovery by 14 months [ ].
Together, these findings support a link between immune activity and symptom onset and progression in genetic mitochondrial disease.
Though the precise mechanisms underpinning this link are yet to be defined, and may differ by form of mitochondrial disease or immune stress, some clues exist.
For example, there is a substantial body of literature on sepsis demonstrating that the septic state can cause mitochondrial dysfunction, and that sepsis-induced mitochondrial dysfunction mediates some of the pathologic consequences of sepsis including lactic acidosis and multiple organ failure see [ , , , , ] for detailed reviews on this topic. Energetics defects, ROS, and metabolic decompensation are thought to be the major pathways involved in this setting.
Accordingly, multiple, non-mutually exclusive, processes are likely involved in linking immune activation to symptom onset or worsening in mitochondrial disease. Murine models of mitochondrial disease also strongly support an immune-centric model for the pathogenesis of genetic mitochondrial disease Fig.
In and , we published studies demonstrating that high-dose oral or injected rapamycin significantly delays disease onset and extends survival in the Ndufs4 KO mouse model of LS [ , , ]. The benefits of mTOR inhibition were found to be independent of mitochondrial function—mitochondrial respiratory capacity and ETC CI assembly, stability, and levels were all unaffected by treatment—but the precise mechanism underlying the benefits of rapamycin were unresolved at the time.
CSF1R inhibition rescued disease, including both a complete prevention of CNS lesions and a rescue of peripheral symptoms such as metabolic dysfunction and cachexia [ ]. Very recently, the partial benefits provided by low doses of PLX have been independently reproduced by another group [ ]. Together, these data provide strong evidence that LS is an immune-mediated disease.
In light of these data, various other studies support a model where genetic mitochondrial diseases are driven in part by immune-mediated processes. PKC inhibitors were found to slightly, but significantly, attenuate disease and extend survival in this model, supporting a causal role for inflammation [ ]. Whether the immune system contributes to the pathogenesis of other forms of primary genetic mitochondrial disease remains to be causally assessed, but available data does seem to support this possibility.
Alopecia, aberrant bone resorption, and hepatic metabolic dysfunction are peripheral symptoms of disease in the Ndufs4 KO that have been shown to be driven by immune cell hyperactivation and macrophage dysfunction [ ]. Treatment of TK2 deficient mouse model of mtDNA depletion with rapamycin, for example, significantly increased survival, as was seen in the Ndufs4 KO [ ].
In a more recent third model of mtDNA instability, loss of the mitochondrial genome maintenance exonuclease Mgme1 , which causes adult-onset mitochondrial disease in humans, results in severe autoimmune disease with prominent inflammatory renal disease [ ].
Importantly, mTOR activity was found to be hyperactive, and rapamycin rescued grip strength and metabolic defects, supporting a role for mTOR in mitochondrial disease beyond Ndufs4 KO [ ]. Similarly, evidence gathered using the Ndufs4 deficiency as a model of optic neuropathy resulting from ETC CI dysfunction revealed that loss of retinal ganglion cells is at least partially driven by inflammation and responsive to mTOR inhibition [ ].
While the disease is both clinically and genetically diverse, some cases of CMT have been causally linked to genes encoding mitochondria proteins, including mitofusion 2 MFN2 and ganglioside-induced differentiation-associated protein 1 GDAP1 [ ]. Mice heterozygous for a disease-causing Mfn2 mutation also present with microgliosis in the optic nerves and in the lumbar spinal cord [ ]. Few animal studies have tested the relationship between immune activation and symptoms in mitochondrial disease, though available data clearly supports a causal link.
One important recent study aimed at directly assessing the bioenergetic costs of infection demonstrated that viral infection leads to metabolic decompensation and mitochondrial hepatopathy in hepatocyte specific Cox10 knockout mice [ ].
These data demonstrate one mechanism for immune-mediated mitochondrial disease symptom onset precipitated by infection. While these findings have highlighted the importance of immune cell actions in the pathogenesis of primary genetic mitochondrial disorders, evidence from basic research in immune cell regulation by mitochondrial metabolism has made this link ever clearer. For example, a naturally occurring mouse mtDNA variant in mt-Atp8 has been found to control susceptibility to disease in two different models of autoimmune skin disease [ ].
Perhaps most striking, cell-specific deletion of the mitochondrial disease associated ETC CIII component encoding Uqcsrf1 restricted to regulatory T-cells has been found to blunt regulatory T-cell suppressive function to such a severe degree that mice die from rampant autoimmunity within weeks of birth [ ]. Notably, regulatory T-cells were present at normal levels, demonstrating that mitochondrial dysfunction in these cells led to severe defects in function without simply causing their depletion.
Mitochondria are highly immunogenic through several distinct pathways, including potent innate immune pathways. Mitochondria arose during eukaryotic evolution as an endosymbiotic intracellular organelle with bacterial origins.
This bacterial origin has resulted in eukaryotic organisms relying on mitochondria as a critically important intracellular organelle which, somewhat remarkably, happens to have retained multiple components that are sensed as foreign if aberrantly released. Mitochondrial proteins can also activate innate immune pathways.
Formylated methionine is an amino acid present in pathogens and mitochondria, and extra-mitochondrial formylated peptides can induce innate immune responses through formyl-peptide receptors FPRs. While protective against pathogens, FPR signaling mediates tissue inflammation and pathology in settings of ischemia—reperfusion, celiac disease, and pulmonary chemical insults, and have been shown to contribute to neurodegenerative disease [ , ]. Worthy of a separate lengthy discussion see reviews [ , , , ] , these pathways provide ample rationale for further study.
Their roles, if any, in genetic mitochondrial disease remain largely unexplored. A role for the immune system in causally contributing to the pathogenesis of at least a subset of genetic mitochondrial diseases appears increasingly likely as various roles for mitochondria in immune function and autoimmunity are resolved. However, a number of critical questions remain unanswered, and immune-based interventions, particularly those which are untargeted in nature, carry serious caveats and limitations.
In particular, the clinical studies and data discussed here are predominately case reports, which are considered weak evidence for clinical practice [ ]. Case report data must also be interpreted carefully in light of the fact that fluctuations in lesions by MRI and clinical status have been documented in Leigh syndrome in the absence of any intervention [ 99 , , ].
While there are significant barriers to performing well-controlled clinical trials in the setting of ultra-rare genetic diseases, these challenges should not mask the limitations of case reports of observational studies.
None of the discussed pre-clinical therapeutics or clinical immune-targeting therapeutics are approved for use in treating genetic mitochondrial disease. As non-clinicians, we make no effort to advocate for any of the described treatments. Rather, our point in this review is to provide an assessment of current evidence suggesting that immune-mediated processes play a causal role in the pathogenesis of mitochondrial disease.
Significant further work is needed to elucidate the precise mechanisms linking mitochondrial dysfunction, immune dysregulation, and pathology. Efforts to understand the basic biology of mitochondrial disease may lead to more targeted intervention strategies, while future trials may determine that approaches such as plasmapheresis, a minimally invasive and well-tolerated non-FDA regulated procedure, may prove beneficial in some acute settings.
In the context of mitochondrial disease, the critical role of mitochondria as modulators of immunity has been a remarkably underappreciated role of these organelles, with the focus on bioenergetics and ROS dominating attempts at therapeutic intervention.
A review concluded that there was no evidence to support the use of any vitamin or cofactor in treating mitochondrial disease [ ]. Ten years later, solid evidence supporting these approaches is still elusive.
Given the failure of antioxidants, nutritional supplements, and pharmacologic approaches to increasing energetic output to meaningfully alter disease course in either animal models or human clinical trials, it is clear that new approaches should be explored [ ].
The data reviewed here strongly suggest that the role of the immune system in mitochondrial disease warrants substantially greater attention. While we have focused our discussion here on genetic mitochondrial diseases, the findings in this field are likely to be relevant to other forms of disease where mitochondrial dysfunction plays a causal role. Complex multigenic traits include diseases where many genetic loci influence disease, but through individually weak effects often best demonstrate by genome-wide association studies [ ].
While beyond our scope here, we suspect that defining the interplay between immune system activity and mitochondrial function in these diseases will be critical to understanding their pathogenesis. Studies in genetic mitochondrial disease is likely to yield important insight relevant to each of these settings. Gorman GS, et al.
Mitochondrial diseases. Nat Rev Dis Primers. Article PubMed Google Scholar. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab. PubMed Google Scholar. Leber Hereditary Optic Neuropathy. Rahman S, Thorburn D. In: Adam MP et al. GeneReviews R. Seattle, Chinnery PF. Primary Mitochondrial Disorders Overview. The genetics and pathology of mitochondrial disease. J Pathol. Emerging concepts in the therapy of mitochondrial disease.
Biochim Biophys Acta. Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology. J Biol Chem. Ng YS, et al. Mitochondrial disease in adults: recent advances and future promise. Lancet Neurol. The genetics of Leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet. Leigh syndrome: resolving the clinical and genetic heterogeneity paves the way for treatment options. Leigh syndrome: one disorder, more than 75 monogenic causes.
Ann Neurol. Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention. Reynaud-Dulaurier R, et al. Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome.
Mol Ther Methods Clin Dev. Jain IH, et al. Hypoxia as a therapy for mitochondrial disease. Leukocytes mediate disease pathogenesis in the Ndufs4 KO mouse model of Leigh syndrome. JCI Insight. Edmonds JL, et al. The otolaryngological manifestations of mitochondrial disease and the risk of neurodegeneration with infection. Arch Otolaryngol Head Neck Surg. Walker MA, et al. J Allergy Clin Immunol Pract. Kruk SK, et al. Vulnerability of pediatric patients with mitochondrial disease to vaccine-preventable diseases.
Eom S, et al. Cause of death in children with mitochondrial diseases. Pediatr Neurol. Finsterer J. Hematological manifestations of primary mitochondrial disorders. In emergency situations aminoglycosides could be used while the benefits of the drugs are more important then.
Neuromuscular blocking drugs used for anaesthesia In patients with muscle disease these drugs should preferably not be used or, if necessary, under strict monitoring. Specific situation General anaesthesia and surgery The time of fasting before surgery should be as short as possible. During prolonged anaesthesia fluid and caloric intake should be guaranteed by glucose infusion, unless the patient is on a ketogenic diet.
Duration of treatment Side effects may develop when medication is used for a longer period. It must be assessed for each individual patient whether the need for long-term treatment outweighs the possible side effects. Kidney failure Kidneys remove certain medicines from the blood. If the kidneys do not work properly, too much medicine remains in the blood.
This may cause more side effects. High lactic acid in blood Patients with a mitochondrial disease may have an increased blood acidity due to high lactic acid. In that case, drugs that can make the blood acidic should preferably not be used or, if necessary, under regular monitoring of. Are you or a family member affected by mito? Contact Disclaimer Copyright. International Mito Patients. Should be used only in exceptional circumstances. In patients with muscle disease these drugs should preferably not be used or, if necessary, under strict monitoring.
The time of fasting before surgery should be as short as possible. Side effects may develop when medication is used for a longer period.
Metrics details. Genetic mitochondrial diseases represent a significant challenge to human health. These diseases are extraordinarily heterogeneous in clinical presentation and genetic origin, and often involve multi-system disease with severe progressive symptoms.
Mitochondrial diseases represent the most common cause of inherited metabolic disorders and one of the most common causes of inherited neurologic diseases, yet no proven therapeutic strategies yet exist. The basic cell and molecular mechanisms underlying the pathogenesis of mitochondrial diseases have not been resolved, hampering efforts to develop therapeutic agents. In recent pre-clinical work, we have shown that pharmacologic agents targeting the immune system can prevent disease in the Ndufs4 KO model of Leigh syndrome, indicating that the immune system plays a causal role in the pathogenesis of at least this form of mitochondrial disease.
Intriguingly, a number of case reports have indicated that immune-targeting therapeutics may be beneficial in the setting of genetic mitochondrial disease. Here, we summarize clinical and pre-clinical evidence suggesting a key role for the immune system in mediating the pathogenesis of at least some forms of genetic mitochondrial disease. Significant clinical and pre-clinical evidence indicates a key role for the immune system as a significant in the pathogenesis of at least some forms of genetic mitochondrial disease.
Genetic mitochondrial diseases affect over 1 in individuals, are the most common cause of inherited metabolic disorders, and are a major cause of genetic neurological diseases [ 1 ]. Mitochondrial diseases are characterized by both genetic and clinical heterogeneity. Over disease causing genes have been causally linked to genetic mitochondrial disease, including genes in both the mitochondrial and nuclear genomes [ 89101112 ].
The often exceedingly rare individual genetic causes cluster into clinically defined syndromes based on symptoms. Accordingly, there is a great deal of genetic heterogeneity within many individual mitochondrial diseases; for example, over 75 genes have been shown to cause LS alone [ 131415 ]. In general, no clear mechanisms distinguish genes within a given clinical syndrome from those in other syndromes.
Significant clinical heterogeneity in disease onset, course, and severity is perhaps unsurprising given the complex genetic architecture of mitochondrial diseases, but genetic differences alone have yet to explain the variant clinical progression of individual cases.
Mechanistic explanations for the complex pathogenesis of individual genetic mitochondrial diseases, and for the differential pathogenesis of unique syndromes arising from similar primary mitochondrial defects, have been elusive, and clinically proven therapeutics are lacking.
Decades of research focused on the primary molecular sequelae of genetic defects in mitochondrial components, i. While rescuing primary genetic defects in pre-clinical models has become possible in recent years, the lack of clinical therapeutic options is in no small part a consequence of the fact that the mechanistic pathobiology of mitochondrial disease has been poorly studied, leaving few options for therapeutic targeting.
Identification of common pathogenic processes downstream of the primary genetic defects could provide treatments for genetically distinct forms of mitochondrial disease. In a recently published study, we demonstrated that immune cells causally drive CNS lesions in the murine model of LS, the most common form of pediatric mitochondrial disease [ 20 ].
LS is a particularly severe form of mitochondrial disease, with symptoms including cerebellar ataxia, hypotonia, respiratory dysfunction, lactic acidosis, seizures, and progressive symmetric necrotizing lesions in the brain stem and cerebellum, which are a defining feature of the disease. In this study, we demonstrate that targeting immune cells through high-dose leukocyte-specific inhibitors rescued both central nervous system degeneration and systemic disease.
Taken with prior studies probing the benefits of mTOR inhibitors in mitochondrial disease, these data provide strong evidence that the pathogenesis of LS is immune mediated. The potential importance of these findings for the treatment and understanding of mitochondrial disease is clear, and assessment of current knowledge regarding the relationship between immune function and mitochondrial disease in human patients is prudent.
Given the ad-hoc management of mitochondrial disease patients, often as a result of symptom management during extended workups leading to eventual diagnosis, there are a number of case-reports of mitochondrial disease patients being treated with various immune-suppressive interventions.
Here, we provide a brief review of these reports, as well as the pre-clinical evidence from mice. Mitochondrial diseases are remarkably heterogeneous. Clinically distinct mitochondrial disease syndromes such as Leigh syndrome and MELAS differ from each other age of onset, organ system involvement, and specific disease sequelae, but disease course and individual symptoms can differ greatly even among patients with the same diagnosed disorder or causal mutation.
Multi-system mitochondrial disorders are most defined by neurologic, metabolic, and muscular symptoms, but mitochondrial defects can impact every organ system, including the immune system. Altered immune system function is a well-documented possible sequalae of genetic mitochondrial dysfunction, but available data indicate that the nature of immune system involvement is extremely complex and very poorly understood. Recent data, detailed below, clearly demonstrate that aberrant immune activation plays a key causal role in the pathogenesis of some forms of genetic mitochondrial disease discussed below.
However, reduced or impaired immune function is a source of acute medical distress in mitochondrial disease, and infections are a major cause of morbidity and mortality in these patients; many experience recurrent infections and delayed recovery following infection, and in some studies sepsis and pneumonia are the most common proximal causes of death [ 21222324 ].
Many mitochondrial disease patients are evaluated for immune deficiency during the diagnosis process. These striking data not only raise clinically and scientifically significant questions about the nature of immune system defects in mitochondrial disease, but also highlight how much we do not yet know about these disorders. In addition to reports associating mitochondrial disease in toto with immune dysfunction, some individual mitochondrial diseases are clearly associated with specific immune defects.
Low white blood cell counts leukopenia have been reported in multiple forms of mitochondrial disease. Cytochrome C oxidase COX activity has been shown to influence T-cell functions in a sub-population dependent manner and lead to immune deficiency, while COX defects in mice impair B-cell positive selection [ 2930 ].
Also in mice, mitochondrial CIII function has been shown to be important for antigen-specific T-cell activation and invariant NK cell development and function [ 3132 ].
Our aim here is to summarize evidence linking immune activity to disease pathogenesis in genetic mitochondrial disease, so a full review of immunometabolism and the role of mitochondria in immune system function is beyond our scope; many high-quality literature reviews expand on these topics for some examples, see [ 33343536 ].
An array of evidence from case reports and natural history studies suggests immune involvement in the pathogenesis of genetic mitochondrial diseases see Fig. Clinical evidence of immune-mediated disease pathogenesis in the setting of genetic mitochondrial disease. In LHON, progressive damage and functional compromise of the optic nerve results in vision loss.
Vascular abnormalities and swelling can be detected early in disease. Though direct evidence for immune involvement in humans is sparse, some data suggests that early-stage LHON is responsive to corticosteroids [ 3738 ]. MS has been causally linked to inflammation, while evidence increasingly supports a role for mitochondrial dysfunction [ 414243 ]. Mitochondrial disease arising from defects in mitochondrial apoptosis inducing factor 1 AIFM1 can cause a wide range of symptoms including encephalomyopathy, cerebellar ataxia, peripheral neuropathy, etc.
Clinical evidence for immune involvement is minimal see pre-clinical section belowbut a patient with particularly severe disease presented with follicular bronchiolitis, a rare non-neoplastic B-cell hyperplasia typically associated with genetic immune defects, acquired immunodeficiencies, or autoimmune disease [ 4452 ].
In Barth syndrome, while patients experience recurrent bacterial infections due to neutropenia, they also have persistently elevated plasma levels of the inflammatory cytokine interleukin 6 IL-6consistent with chronic inflammation, which are thought to contribute to muscle-wasting [ 535455 ].
Mitochondrial leukoencephalopathy are mitochondrial disorders with CNS white matter involvement. MRI of the brains of patients with these disorders reveal white matter pathology including contrast enhancement and diffusion restriction consistent with blood brain barrier breakdown and neuroinflammation [ 56 ].
Reactive microgliosis was also observed by histology in a subset of patients, though there was no evidence of peripheral immune cells in the CSF.
Evidence for chronic inflammation has also been reported in patients with mutations in POLG1 encoding a subunit of the mtDNA polymerase : two case reports found oligoclonal banding in CSF versus plasma consistent with CSF autoimmunity and typically seen in multiple sclerosis, where a causal role for immune involvement is well accepted [ 5758596061 ]. Transcriptomic analysis of muscle biopsies from TK2 deficiency patients has revealed increased expression of genes associated with inflammation [ 64 ].
Inflammation appears to play a role in the pathogenesis of the mitochondria-associated iron accumulation disease Friedreich ataxia FRDA. In addition to its use in treating immunoglobulin deficiencies, intravenous immunoglobulin IVIG therapy is a well-documented immune-suppressing therapeutic strategy used in autoimmune disorders such as systemic lupus erythematosus, antiphospholipid syndrome, Kawasaki disease, demyelinating diseases, autoimmune neuromuscular disease, and scleroderma [ 6970 ].
In mitochondrial disease, a patient with a confirmed mitochondrial myopathy was found to have muscle T-cell infiltration upon biopsy and showed significant clinical improvement after IVIG therapy [ 71 ]. In another case report, three children with genetically and clinically distinct forms of mitochondrial disease were treated with immune targeting therapies. One responded well to corticosteroids alone, another stabilized with corticosteroids and the B-cell depleting drug rituximab, another failed to respond to corticosteroids but showed marked improvement following IVIG [ 72 ].
Perhaps most dramatically, an adult-onset Leigh syndrome patient was given plasmapheresis to treat a suspected autoimmune disease and experienced resolution of symptoms prior to the confirmation of a Leigh syndrome diagnosis, with a known causal homoplasmic ATP6A mtDNA variant and characteristic CNS lesions [ 73 ].
Strikingly, the patient remitted following therapy, but with IVIG once again showed substantial improvements in symptoms. The authors concluded simply that the mechanism of benefit was unknown, but that ATP6A Leigh syndrome may involve underlying autoimmune mechanisms. Corticosteroids, as mentioned above, also appear to provide significant, and at times persistent, benefits in genetically and clinically distinct forms of mitochondrial disease [ 74 ].
These include MELAS [ 7576777879 ], mitochondrial neurogastrointestinal encephalopathy MNGIE [ 80 ], mitochondrial myopathy [ 81 ], mitochondrial encephalomyopathy [ 8283 ], mitochondrial leukoencephalopathy [ 56 ], and other forms of mitochondrial disease [ 848586 ]. The clinical reversal of disease was so striking in some cases, as in the full reversal of CNS symptoms in MELAS with subsequent dependency on corticosteroids to prevent relapse, that authors suggested corticosteroids should be standard treatments in mitochondrial disease [ 76 ].
However, while corticosteroids may benefit many forms of mitochondrial disease, a review of case reports found that they are likely detrimental in one form of mitochondrial disease, Kearns-Sayre syndrome [ 74 ].
Whether a different immune targeting approach would yield benefits, or immune involvement is not universal in mitochondrial disease, remains to be determined. In response to preclinical data from the Ndufs4 KO mouse detailed belowmechanistic target of rapamycin mTOR inhibitors have also recently been tested in small cohorts of mitochondrial disease patients. A recent trial reported the use of everolimus in two pediatric mitochondrial disease patients reported mixed responses [ 87 ].
A 2 year-old Leigh syndrome patient homozygous for the known pathogenic c. In a separate study four post-transplant MELAS patients in terminal decline were transitioned from calcineurin inhibitors to mTOR inhibitors, and all four showed substantial improvement in over the following months [ 88 ]. While the answer to these questions is complex, immune functions appear to be one potent contributor to both onset and severity of genetic mitochondrial disease.
Mitochondrial disease can present prenatally or at birth, but in many patients, symptoms do not appear until later. Adult-onset mitochondrial disease is well-documented, even in classically pediatric syndromes such as LS.
Even in those with pediatric onset it is notable that symptoms are frequently absent at birth in many forms of mitochondrial disease. Disease onset can vary widely both when comparing different clinically defined mitochondrial disease syndromes, as with the generally adult-onset MELAS versus typically pediatric onset Leigh syndrome, but also occur between patients with the same clinical disorder.
It is hard to reconcile any post-natal onset of serious multi-system degenerative disorders such as LS, particularly in cases of adult-onset disease, with models where mitochondrial bioenergetics or ROS directly drive disease pathobiology.
While a robust link has not yet been established, viral infection and fever have been reported to coincide with symptom onset in mitochondrial disease [ 21909192939495 ].
For example, in three unrelated patients with POLG mutations, symptom onset followed infection with human herpesvirus 6 or Borrelia [ 9697 ]. These patients all presented with severe seizures and rapid progressive neurodegeneration despite antivirals and antibiotics treatment and were eventually diagnosed with mitochondrial disease caused by POLG.
Borrelia infection has also been associated with the onset of disease in a case of LHON [ 98 ]. It has been hypothesized that this link is due to the energetic stress associated with induction of an immune response [ 91 ].
In light of the evidence for an immunologic origin of disease in LS it seems reasonable that it is the upregulated immune responses themselves that trigger disease onset. Testing this possibility will require careful study using animal models.
Similarly, while genetic mitochondrial diseases are progressive, the progression of symptoms is not linear—patients experience periods of relative stability interrupted by periods of deterioration. Reasons for ebbs and flow in disease are likely complex, but infections are one important factor.
Moreover, there was a temporal delay of about a week between infection and neurodegenerative event—a timeframe the authors note is similar to that observed in Reye syndrome and suggest could be related to the induction of inflammatory cytokines or cellular mediators of immunity. These findings are notable in light of recent findings linking mitochondrial function to T-cells immune regulatory function in mice discussed below.
Finally, it appears possible that some mitochondrial defects only present when uncovered by an immunologic insult. In at least one case, mitochondrial leukoencephalopathy which may have been precipitated by infection appeared reversible after recovery from acute illness—an infant with a DARS2 mutation experienced dramatic neurological deterioration after a respiratory tract infection at 9 months of age but gradually improved several months after resolution of the infection until nearly complete recovery by 14 months [ ].
Together, these findings support a link between immune activity and symptom onset and progression in genetic mitochondrial disease. Though the precise mechanisms underpinning this link are yet to be defined, and may differ by form of mitochondrial disease or immune stress, some clues exist. For example, there is a substantial body of literature on sepsis demonstrating that the septic state can cause mitochondrial dysfunction, and that sepsis-induced mitochondrial dysfunction mediates some of the pathologic consequences of sepsis including lactic acidosis and multiple organ failure see [, ] for detailed reviews on this topic.
Energetics defects, ROS, and metabolic decompensation are thought to be the major pathways involved in this setting. Accordingly, multiple, non-mutually exclusive, processes are likely involved in linking immune activation to symptom onset or worsening in mitochondrial disease.
Murine models of mitochondrial disease also strongly support an immune-centric model for the pathogenesis of genetic mitochondrial disease Fig. In andwe published studies demonstrating that high-dose oral or injected rapamycin significantly delays disease onset and extends survival in the Ndufs4 KO mouse model of LS [, ]. The benefits of mTOR inhibition were found to be independent of mitochondrial function—mitochondrial respiratory capacity and ETC CI assembly, stability, and levels were all unaffected by treatment—but the precise mechanism underlying the benefits of rapamycin were unresolved at the time.
CSF1R inhibition rescued disease, including both a complete prevention of CNS lesions and a rescue of peripheral symptoms such as metabolic dysfunction and cachexia [ ].
Mitochondrial disorders are a group of metabolic conditions caused by During stroke-like episodes, steroids may be safely used and could play some. Medicines that are toxic to mitochondrial functions should be avoided in patients with mitochondrial disorders. Due to the great diversity in. Genetic mitochondrial diseases represent a significant challenge to corticosteroids may benefit many forms of mitochondrial disease. Patients suspected of having a primary mitochondrial disease, but in whom the diagnosis has not Steroids, eg hydrocortisone, dexamethason, prednisone. Although there is no causal treatment of mitochondrial disorders (MIDs) yet myopathy with cardiomyopathy, lactic acidosis and response to prednisone and. Payette H, et al. Pediatr Neurol. Availability of data and materials Not applicable.It is important to remember that side effects can occur with any medicine in any patient. This can affect anyone taking the medicine and may not be related to your mitochondrial disease. It is therefore essential that you take the advice of your doctor and read the information given with the medicine. This is a list of medicines drugs that should be avoided or used with caution in people affected by a primary mitochondrial disease. Patients suspected of having a primary mitochondrial disease, but in whom the diagnosis has not yet been confirmed by doctors, may also consult this list.
The list was compiled by a group of experts in mitochondrial disease doctors, pharmacists and scientists , after careful consideration and consultation. This is a genetic disorder that affects the function of the mitochondria.
Mitochondria are tiny power stations present inside our cells and are responsible for making the energy that powers everything that happens inside our bodies. Primary mitochondrial disease is diagnosed by doctors after a series of tests that may include blood and urine tests, brain scan MRI , muscle biopsy and, most importantly, genetic testing. Currently, there are no cures for most mitochondrial diseases.
This means that supportive treatments and medicines are extremely important. These include medicines for treating seizures anticonvulsants , antibiotics for treating bacterial infections, medicine for managing pain, controlling fevers, treating diabetes and heart disease, and for administering general anaesthesia safely when an operation is needed.
We saw that the existing list of medicines thought to be unsuitable contraindicated in patients with mitochondrial disease was very long and contained drugs that we felt could be useful in treating patients with mitochondrial disease. Therefore, we thought it was important that each medicine on the list was reviewed and updated with the latest clinical and scientific evidence.
Our group consisted of sixteen doctors, pharmacists and scientists and each was assigned a group of drugs to evaluate. These experts then spent two months researching the evidence for whether the medicine was harmful for mitochondrial disease patients for each of the drugs assigned to them.
The group then met for a two day workshop to discuss the evidence for more than 50 drugs and decide whether or not they could safely be used in mitochondrial disease. This process of evaluating evidence is known as a Delphi workshop, and is widely accepted as a valid scientific method. After a thorough review of the evidence, we concluded that most drugs on the previous list could be used safely in people affected by primary mitochondrial disease.
The drug valproic acid an antiepileptic drug also known as sodium valproate or Epilim should not be given to patients with mutations in a gene called POLG and not used in any patient who could have a primary mitochondrial disease until POLG mutation is ruled out. Table 2 also lists drugs that need careful evaluation and situations in which doctors may want to change the way that these medicines are used or prescribed for patients affected by particular types of mitochondrial disease.
It is very important that you consult your doctor whenever you are unwell. You may, however, wish to share the "List of medicines considered safe to use" and the "List with points of attention" with your doctor s and discuss with them what this means for you and your particular type of mitochondrial disease. Maaike C. Gorman David A. Brown Mitchell E. Pitceathly Frans G.
Russel Kristin N. Varhaug Tom J. Schirris see reference article for more background. List of medicines to be used with caution in primary mitochondrial disease. Font size. February It is important to remember that side effects can occur with any medicine in any patient.
Table 1. Table 2. Should not be used in patients with liver disease. In emergency situations aminoglycosides could be used while the benefits of the drugs are more important then. Neuromuscular blocking drugs used for anaesthesia In patients with muscle disease these drugs should preferably not be used or, if necessary, under strict monitoring.
Specific situation General anaesthesia and surgery The time of fasting before surgery should be as short as possible. During prolonged anaesthesia fluid and caloric intake should be guaranteed by glucose infusion, unless the patient is on a ketogenic diet. Duration of treatment Side effects may develop when medication is used for a longer period. It must be assessed for each individual patient whether the need for long-term treatment outweighs the possible side effects.
Kidney failure Kidneys remove certain medicines from the blood. If the kidneys do not work properly, too much medicine remains in the blood. This may cause more side effects. High lactic acid in blood Patients with a mitochondrial disease may have an increased blood acidity due to high lactic acid. In that case, drugs that can make the blood acidic should preferably not be used or, if necessary, under regular monitoring of. Are you or a family member affected by mito? Contact Disclaimer Copyright.
International Mito Patients. Should be used only in exceptional circumstances. In patients with muscle disease these drugs should preferably not be used or, if necessary, under strict monitoring. The time of fasting before surgery should be as short as possible. Side effects may develop when medication is used for a longer period.
Kidneys remove certain medicines from the blood. Patients with a mitochondrial disease may have an increased blood acidity due to high lactic acid.
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