Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome

Daneshgar, Nastaran; Leidinger, Mariah; Le, Stephanie; Hefti, Marco M.; Prigione, Alessandro; Dai, Dao-Fu

doi:10.3389/fnins.2022.1068498

Cited by 8 publications

(7 citation statements)

References 32 publications

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“…One limitation of our current study is the use of a small molecule approach that has a systemic effect and is not able to answer the cell-type specificity of our treatment, but it may facilitate the translation to clinical therapeutics. Treatment options for LS patients are very limited; however, promising pre-clinical studies using the same germline Ndufs4 −/− mouse model have identified potential new therapies to alleviate LS pathologies, including rapamycin [31], chronic hypoxia [32], supplementation of NAD + [24], and microglial ablation [33]. Chronic hypoxia decreased toxic oxygen metabolites and has been shown to improve survival, body weight, body temperature, behavior, neuropathology, disease biomarkers, and brain NAD + concentration in LS mice [34].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice

et al. 2023

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Mitochondrial oxidative stress has been implicated in aging and several cardiovascular diseases, including heart failure and cardiomyopathy, ventricular tachycardia, and atrial fibrillation. The role of mitochondrial oxidative stress in bradyarrhythmia is less clear. Mice with a germline deletion of Ndufs4 subunit respiratory complex I develop severe mitochondrial encephalomyopathy resembling Leigh syndrome (LS). Several types of cardiac bradyarrhythmia are present in LS mice, including a frequent sinus node dysfunction and episodic atrioventricular (AV) block. Treatment with the mitochondrial antioxidant Mitotempo or mitochondrial protective peptide SS31 significantly ameliorated the bradyarrhythmia and extended the lifespan of LS mice. Using an ex vivo Langendorff perfused heart with live confocal imaging of mitochondrial and total cellular reactive oxygen species (ROS), we showed increased ROS in the LS heart, which was potentiated by ischemia-reperfusion. A simultaneous ECG recording showed a sinus node dysfunction and AV block concurrent with the severity of the oxidative stress. Treatment with Mitotempo abolished ROS and restored the sinus rhythm. Our study reveals robust evidence of the direct mechanistic roles of mitochondrial and total ROS in bradyarrhythmia in the setting of LS mitochondrial cardiomyopathy. Our study also supports the potential clinical application of mitochondrial-targeted antioxidants or SS31 for the treatment of LS patients.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice

et al. 2023

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“…In previous reports, we and others described that decreasing the neuroimmune response by depleting microglial cells has beneficial effects in Ndufs4 KO mice [ 17 , 18 , 37 ]. In this study, we wanted to assess whether a chronic induction of a neuroinflammatory state prior to neuropathology onset could affect the pathology of Ndufs4 KO mice.…”

Section: Resultsmentioning

confidence: 99%

Interleukin-6-elicited chronic neuroinflammation may decrease survival but is not sufficient to drive disease progression in a mouse model of Leigh syndrome

Aguilar,

Canal,

Comes

et al. 2024

J Inflamm

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Background Mitochondrial diseases (MDs) are genetic disorders characterized by dysfunctions in mitochondria. Clinical data suggest that additional factors, beyond genetics, contribute to the onset and progression of this group of diseases, but these influencing factors remain largely unknown. Mounting evidence indicates that immune dysregulation or distress could play a role. Clinical observations have described the co-incidence of infection and the onset of the disease as well as the worsening of symptoms following infection. These findings highlight the complex interactions between MDs and immunity and underscore the need to better understand their underlying relationships. Results We used Ndufs4 KO mice, a well-established mouse model of Leigh syndrome (one of the most relevant MDs), to test whether chronic induction of a neuroinflammatory state in the central nervous system before the development of neurological symptoms would affect both the onset and progression of the disease in Ndufs4 KO mice. To this aim, we took advantage of the GFAP-IL6 mouse, which overexpresses interleukin-6 (IL-6) in astrocytes and produces chronic glial reactivity, by generating a mouse line with IL-6 overexpression and NDUFS4 deficiency. IL-6 overexpression aggravated the mortality of female Ndufs4 KO mice but did not alter the main motor and respiratory phenotypes measured in any sex. Interestingly, an abnormal region-dependent microglial response to IL-6 overexpression was observed in Ndufs4 KO mice compared to controls. Conclusion Overall, our data indicate that chronic neuroinflammation may worsen the disease in Ndufs4 KO female mice, but not in males, and uncovers an abnormal microglial response due to OXPHOS dysfunction, which may have implications for our understanding of the effect of OXPHOS dysfunction in microglia.

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“…The brain pathology in LS patients shows white matter vacuolization, increased vascularity and gliosis, microglial expansion, and increased IL-6 levels in the cerebellum and brainstem in NDUFS4 -/- mice, and neuroinflammation is indicated in LS patients’ brains 27 . The antioxidative and anti-ferroptotic effects of apomorphine and its derivatives need to be evaluated for pathological alterations when administered to the brain tissue.…”

Section: Discussionmentioning

confidence: 99%

Synthetic aporphine alkaloids are potential therapeutics for Leigh syndrome

Kobayashi,

Miyauchi,

Jimbo

et al. 2024

Sci Rep

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Mitochondrial diseases are mainly caused by dysfunction of mitochondrial respiratory chain complexes and have a variety of genetic variants or phenotypes. There are only a few approved treatments, and fundamental therapies are yet to be developed. Leigh syndrome (LS) is the most severe type of progressive encephalopathy. We previously reported that apomorphine, an anti- “off” agent for Parkinson’s disease, has cell-protective activity in patient-derived skin fibroblasts in addition to strong dopamine agonist effect. We obtained 26 apomorphine analogs, synthesized 20 apomorphine derivatives, and determined their anti-cell death effect, dopamine agonist activity, and effects on the mitochondrial function. We found three novel apomorphine derivatives with an active hydroxy group at position 11 of the aporphine framework, with a high anti-cell death effect without emetic dopamine agonist activity. These synthetic aporphine alkaloids are potent therapeutics for mitochondrial diseases without emetic side effects and have the potential to overcome the low bioavailability of apomorphine. Moreover, they have high anti-ferroptotic activity and therefore have potential as a therapeutic agent for diseases related to ferroptosis.

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Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome

Cited by 8 publications

References 32 publications

Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice

Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice

Interleukin-6-elicited chronic neuroinflammation may decrease survival but is not sufficient to drive disease progression in a mouse model of Leigh syndrome

Synthetic aporphine alkaloids are potential therapeutics for Leigh syndrome

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