bims-mitmed 2026-09-20 papers

Mamm Genome. 2026 Sep 18. pii: 108. [Epub ahead of print]37(1):

The role of impaired mitochondrial function in neurological manifestations of mitochondrial diseases.

Danielle Brister, Mariana Zarate-Mendez, Denisa Hathazi, Rita Horvath.

Mitochondria are essential organelles responsible for cellular energy production and the regulation of key metabolic and signalling pathways. Their function depends on the coordinated expression of both mitochondrial and nuclear genomes, and mitochondrial dysfunction leads to a diverse group of mitochondrial diseases. The nervous system is particularly vulnerable to mitochondrial dysfunction due to the high energetic demands and complex morphology of neurons. Neurons rely heavily on mitochondrial ATP production to support processes such as synaptic transmission, axonal transport, and calcium homeostasis, which are tightly regulated by mitochondrial dynamics, intracellular trafficking, and quality control mechanisms. In mitochondrial diseases, impairment of these processes contributes to a range of neurological manifestations, including epilepsy, stroke-like episodes, Leigh syndrome, ataxia, and peripheral neuropathy. Despite the ubiquitous presence of mitochondria, neuronal vulnerability varies between distinct neuronal populations, reflecting differences in neuronal morphology and metabolic demands. This review summarises key mechanisms underlying neuronal susceptibility in mitochondrial disease and highlights how defects in mitochondrial bioenergetics, dynamics, and transport contribute to characteristic neurological phenotypes. Understanding these mechanisms may provide insights into tissue-specific vulnerability and identify potential therapeutic targets to treat mitochondrial diseases and other neurodegenerative disorders associated with mitochondrial mechanisms.

DOI: https://doi.org/10.1007/s00335-026-10278-5

Nature. 2026 Sep 18.

First for RNA therapy: man with rare motor-neuron disease improves after treatment.

Rachel Fieldhouse.

Keywords: Brain; Diseases; Gene therapy; Medical research

DOI: https://doi.org/10.1038/d41586-026-02945-z

Int J Mol Sci. 2026 Aug 28. pii: 7734. [Epub ahead of print]27(17):

Mitochondrial Distress Signals at the Heart-Liver Interface: Molecular Links Between MASLD and Heart Failure.

Xing Yang, Kun Cheng, Chen Chen, Yuxin Zhang, Dao Wen Wang.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and heart failure (HF) frequently coexist within a shared cardiometabolic environment, yet their mitochondrial abnormalities are stage- and phenotype-dependent rather than uniform. In MASLD, mitochondrial adaptation evolves from increased oxidative metabolism in early steatosis toward impaired respiratory flexibility, oxidative stress, and defective quality control with disease progression, whereas the failing myocardium develops reduced energetic reserve and altered substrate utilization. These organ-specific disturbances can modify mitochondria-linked metabolites, mitochondrial damage-associated molecular patterns, stress-responsive endocrine mediators, and extracellular vesicle-associated mitochondrial cargo. However, similar mitochondrial abnormalities or circulating signals in the liver and heart do not by themselves establish direct inter-organ communication. This review distinguishes shared systemic drivers and organ-intrinsic mitochondrial stress from source-resolved cardio-hepatic signaling, highlighting hepatic ketogenesis, fibroblast growth factor 21 (FGF21), mitochondrial DNA (mtDNA)-dependent inflammatory pathways, and extracellular vesicle-mediated cargo transfer as mechanistically distinct examples with different levels of evidence. We further discuss biomarker limitations, HF-related hemodynamic liver injury, and therapeutic strategies ranging from established cardiometabolic unloading to emerging mitochondria-centered interventions. A stage-, phenotype-, and source-resolved framework may improve interpretation of mitochondrial signals and guide future mechanistic and translational studies in the MASLD-HF overlap.

Keywords: cardio-hepatic crosstalk; heart failure; metabolic dysfunction-associated steatotic liver disease; mitochondrial distress signaling; mitochondrial dysfunction

DOI: https://doi.org/10.3390/ijms27177734

Int J Mol Sci. 2026 Aug 27. pii: 7678. [Epub ahead of print]27(17):

Mitochondrial Control of Myelination, Bioenergetics, Oxidative Stress, and the Pathogenesis of Optic Neuropathies.

Haya Sahibzada, Rizwan Malik, Khaled K Abu-Amero.

Myelination, mitochondrial bioenergetics, and oxidative stress are usually discussed as separate problems in optic nerve disease. This review draws them together and reads the published evidence through a single variable, the balance between the energy a retinal ganglion cell (RGC) axon spends and the energy its mitochondria can supply. We review the role of myelin in conduction and axonal support, the mitochondrial cost of building and maintaining it, the vulnerability of oligodendrocytes and myelin to oxidative injury, and the nuclear control of mitochondrial output. We summarize the inherited optic atrophies linked to OPA1, OPA3, AFG3L2, SPG7, and TMEM126A, and set these primary mitochondrial disorders against the immune-mediated demyelinating optic neuropathies. Published studies already support several parts of this picture, including the energetic cost of demyelination, the mitochondrial dependence of RGC axons, and oxidative injury in inflammatory lesions. Drawing on that evidence, we propose, as a testable hypothesis rather than a settled mechanism, that optic nerve degeneration is favored when axonal ATP demand outruns mitochondrial supply, most sharply where the axon crosses from its unmyelinated to its myelinated segment near the lamina cribrosa. We use this framework to separate initiating lesions from disease modifiers and downstream consequences, and to set out therapeutic predictions open to experimental and clinical tests.

Keywords: OPA1; bioenergetics; demyelination; mitochondria; myelination; optic neuropathy; oxidative stress; retinal ganglion cell

DOI: https://doi.org/10.3390/ijms27177678

Int J Mol Sci. 2026 Aug 28. pii: 7710. [Epub ahead of print]27(17):

Cox7a2l Variation Influences Complex III and Mitochondrial Supercomplex Differences in 3xTG-AD Mixed-Background Mice.

Wenzhuo Ma, Clarissa Cavarsan, Lauren F Bazinet, Scarlett M Silvia, Joseph Owusu-Sarfo, Janet Atoyan, Judianne Davis, William E Van Nostrand, John K Robinson, Richard T Clements.

Mitochondrial dysfunction, including impaired respiration and increased reactive oxygen species (ROS), is an early feature of Alzheimer's disease (AD) models. Electron transport chain supercomplexes (mSCs) regulate respiratory efficiency and ROS generation, yet genetic determinants of mSC organization in AD models remain underappreciated. Cox7a2l is known to promote CIII2/CIV association and CIV incorporation into mSCs. We examined the commonly used mixed-background B6;129S 3xTg-AD mice and B6129SF2/J controls aged 12-15 months, as well as specific rat AD models for changes in mSC organization using blue and clear native-PAGE and DIA-MS. BN and CN-PAGE revealed a marked shift toward larger mSC assemblies in 3xTg-AD mice and a distinct ~650 kDa assembly of complex III absent from controls. Gene sequencing showed that 3xTg-AD mice retained the full-length Cox7a2l variant similar to 129S strains, whereas controls predominantly carried a shortened C57BL/6-associated variant. DIA-MS identified greatly increased Cox7a2l in differential mSC bands. Similar changes were found in 3xTg-AD heart tissue. In contrast, AD rat models and their controls, all expressing full-length Cox7a2l, did not exhibit comparable mSC differences. These findings suggest Cox7a2l genotype as a determinant of mSC organization and highlight the need to account for genetic background when interpreting mSC-dependent mitochondrial phenotypes in mixed-background 3xTg-AD studies. This distinction is essential for accurately separating strain-dependent effects from AD-associated mitochondrial changes.

Keywords: Alzheimer’s disease; COX7RP; SCAF1; mitochondrial supercomplex; respiration; supercomplex

DOI: https://doi.org/10.3390/ijms27177710