The precise mechanisms driving mitochondrial pathology and subsequent neurodegeneration in MS remain incomplete

The gap

Evidence profile

Sourced from the future work and stated research gap of the source papers, classified as general, spanning 3 journals. Those papers have been cited 1 times in total.

Supporting evidence — 3 representative gaps

• Mitochondrial dysfunction in neurodegenerative disorders: mechanisms and therapeutic advances (2026) · Molecular Biomedicine · doi

  Mitochondrial dysfunction has emerged as a unifying pathological hub across the spectrum of neurodegen- erative diseases. From the well-characterized monogenic optic neuropathies and Friedreich’s ataxia to the com- plex, multifactorial pathology of Alzheimer’s and Parkin- son’s diseases, the shared themes of bioenergetic failure, disrupted dynamics, defective quality control, and neuro- inflammatory amplification underscore the central role of mitochondrial health in neuronal survival. Importantly, the approval of omaveloxolone for Friedreich’s ataxia and Idebenone for LHON demonstrates that mitochondria- targeted therapies can achieve regulatory milestones, providing a framework for future drug development. Studies of inherited optic neuropathies have high- lighted that discrete genetic lesions in mtDNA or nDNA converge on mitochondrial dysfunction, ultimately trig- gering the demise of selectively vulnerable neurons. The persistent enigmas of these disorders, including incom- plete penetrance, delayed onset related to age, and sex bias, highlighting the complex crosstalk between genetic susceptibility and other modifying factors, offering a new perspective to investigate the broader dynamics of neu- rodegenerative processes. A better understanding of the molecular basis of mitochondrial dysfunction is needed. Cellular mod- els, including cybrids (a hybrid cell with nuclear genes from one cell and mitochondrial genes from another cell), as well as differentiated cybrids with neuronal like properties, can complement genetic analysis like link- age analysis of extensive pedigrees and deep sequencing of the mitochondrial genome. Moreover, the establish- ment of reliable animal models that faithfully mimics optic nerve degeneration observed in humans, such as patient-derived retinal organoids and non-human pri- mate models of optic neuropathy, would be a valuable resource for testing innovative and promising therapeutic interventions. These advanced models should be coupled with cutting-edge imaging modalities, such as fluores- cence lifetime imaging microscopy, to enable real-time monitoring of mitochondrial functions and therapeutic response in vivo. Overcoming biological barriers is another universal challenge. For the eye and the brain alike, the develop- ment of next-generation delivery platforms, such as engi- neered AAV capsids with enhanced retinal tropism and mitochondrially targeted nanoparticles, can help improve therapeutic biodistribution while minimizing systemic exposure. Additionally, a more comprehensive and system- atic investigation of the progression of these diseases is needed. Long-term follow-up incorporating neuroimag- ing, functional assessments, and proteomic analysis may help define the most

  generalfuture work
  Keywords: mitochondrial optic dysfunction diseases genetic cell models therapeutic well neuropathies friedreich ataxia dynamics neuronal targeted
• The Role of Apoptosis and Ferroptosis in Primary Mitochondrial Diseases: Mechanisms and Pathogenesis (2026) · International Journal of Molecular Sciences · cited 1× · doi

  Mitochondrial diseases are complex pathological states with multiple interconnected mechanisms of cell death. In this context, apoptosis and ferroptosis act not as isolated processes but as complementary pathways. They are united by common triggers—critical accumulation of mitochondrial ROS, depletion of the GSH pool, and disruption of iron homeostasis—and by points of molecular crosstalk (p53, cytochrome c and cardiolipin, BCL-2 proteins). The pronounced tissue specificity, for example, selective vulnerability of retinal gan- glion cells in LHON or cardiomyocytes under iron overload, necessitates a personalized approach, in which diagnostics should rely on the integration of genetic profiling (mtDNA and exome) and functional tests such as monitoring the dynamics of LIP (labile iron pool) and mitochondrial lipid peroxidation. It must be acknowledged that the evidence base for the causal role of ferroptosis in PMDs remains largely indirect. The majority of avail- able data have been obtained in cell models using pharmacological inducers (erastin, RSL3) that do not reproduce the genetic nature of the mitochondrial defect, or based on immunohistochemical markers of lipid peroxidation without functional verification of ferroptosis. A priority is to conduct studies directly on tissue biopsies from patients with PMDs, employing cryo-electron microscopy and spatial lipidomics. A new therapeutic horizon is opened by a strategy of combined inhibition, including mitochondria-targeted antioxidants (SkQ1, MitoTEMPO, MitoQ) that block lipid peroxida- tion directly at its site of initiation; modulators of the xCT–GPX4 axis and specific agents such as EPI-743 (vatiquinone), which have demonstrated efficacy in rescuing cells of pa- tients with Leigh syndrome and mitochondrial epilepsy; and iron chelators (deferoxamine, dexrazoxane) and mPTP inhibitors (cyclosporin A) that prevent the massive release of pro-death factors. Priority tasks in mitochondrial medicine remain the elucidation of the mechanisms of “switching” between death pathways and the development of systems for targeted drug delivery to organelles, which will minimize systemic toxicity and improve patient survival. Author Contributions: Conceptualization, A.K. and A.S.; resources, A.K.; data curation, A.K.; writing—original draft preparation, A.K.; writing—review and editing, A.S.; visualization, A.K.; supervision, S.K. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: No new data were created or analyzed in this study. Data sharing is not applicable to this article. Conflicts of Interest: The authors declare no conflicts of interest. https://doi.org/10.3390/ijms27135931 Int. J. Mol. Sci. 2026, 27, 5931 24 of 32

  generalfuture work
  Keywords: mitochondrial iron death ferroptosis lipid statement applicable mechanisms cell pathways pool tissue cells genetic functional
• Decoding multiple sclerosis: linking autoimmunity, and nutrition/environmental factors to mitochondrial dysfunction and therapeutic opportunities (2026) · 3 Biotech · doi

  The precise mechanisms driving mitochondrial pathology and subsequent neurodegeneration in MS remain incomplete. There is a need for a better understanding of the interplay between mitochondrial dynamics and the molecular mechanisms governing mitochondrial function. The development of targeted therapeutics designed to preserve mitochondrial integrity and halt disease progression is a key research gap.

  generalstated research gapevidence 5/5
  Keywords: precise mechanisms driving mitochondrial pathology subsequent neurodegeneration remain

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