Editorial: Recent Advances in Mitochondrial Dysfunction and Therapeutics for Neurodegeneration and Aging

Monokesh K Sen^1*Keagan Dunville^2*Nicole Miles³Michelle Newbery³Neville Ng^3*Lezanne Ooi^3*

• ¹The University of Sydney, Sydney, Australia
• ²Norwegian University of Science and Technology, Trondheim, Norway
• ³University of Wollongong, Wollongong, Australia

Recent estimates indicate that neurological conditions affect over 3.4 billion individuals globally (Steinmetz et al., 2024). A well-established contributor to neurological conditions is the decline of mitochondrial function, responsible for producing over 90% of cellular ATP via oxidative phosphorylation. Mitochondrial dysfunction is closely linked to cellular pathology, and cognitive and motor decline symptoms in neurodegeneration and aging. Common features of mitochondrial dysfunction include excessive reactive oxygen species (ROS) generation, damage to mitochondrial DNA (mtDNA), impaired mitochondrial quality control, and disrupted mitochondrial dynamics (Ng et al., 2024). Subsequent cellular damage includes disrupted protein synthesis, transport, and degradation, increased inflammation, oxidative damage to genomic DNA, lipids, and proteins, aberrant calcium signalling, telomere shortening, senescence, eventual cell death (Ng et al., 2024), contributing to complex protein-nucleic acid mass aggregation and systemic inflammation. Submissions to this Special Topic collection exemplify a range of experimental approaches to analyse mitochondrial aetiology in neurological disorders and aging (Figure 1). These studies highlight the significance of mitochondrial damage, dysfunctional mitochondrial biogenesis and mito-lysosomal clearance, and subsequent neuroinflammation in neurodegenerative diseases and aging, discussed in concluding notes of this editorial. Using iPSC neuronal models with microfluidics to analyse LRRK2 mutation in Parkinson's disease Valderhaug et al. (2024) explored a pilot of a multichambered microfluidic slide and microelectrode arrays, using a Parkinson's disease induced pluripotent stem cell (iPSC) derived line with a LRRK2 G2019S mutation, associated with both familial and sporadic forms, compared against its isogenic control. This combination allowed for the structuring of intrinsic network firing behaviour, mitochondrial membrane potential, kymography, and oxidative stress, with and without the ionotropic glutamate agonist kainic acid. Neurons with the LRRK2 G2019S mutation showed greater neurite outgrowth, increased mitochondrial motility that was decreased with kainic acid stress, decreased mitochondrial anterograde movement, and hyperpolarisation in LRRK2 G2019S networks. While limited to preliminary observations in replicate number, these data demonstrate a multimodal approach to simultaneously analysing neurite density, electrophysiology and mitochondria, that could be applied to other disease models. Mitochondria play a pivotal role in neurodevelopment, and in this special topic collection, several groups investigate the role of mitochondria in sensory and associative cortical systems. Cavestro et al. (2024) investigate the role of Coenzyme A synthase (protein: CoA synthase, encoding gene: Coasy, Chr:11) in mouse in vitro and in vivo knockout models to dissect nuclear-mitochondrial crosstalk relevant to CoA-related disorders. CoA synthase lossof-function mutations drive rare yet debilitating neurodegeneration, such as Coasy proteinassociated neurodegeneration, and neurodevelopmental disorders, including Pontocerebellar Hypoplasia Type 12. Conditional knockouts were generated using a humanised glial fibrillary acidic protein (GFAP) promoter and Coasy flox/flox mice, ensuring loss of CoA synthase in astroglial lineage cells. Intriguingly, GFAP-Coasy mice manifested two distinct, sexindependent phenotypes with motor deficits: early onset (euthanized by postnatal day 20) and late onset (unaffected mortality). Additionally, GFAP-Coasy mice exhibited severe layering deficits in the cortex and cerebellum, demonstrating that embryonic expression of CoA synthase is necessary for inherent cytoarchitectural establishment. Moreover, astroglialspecific expression of nuclear receptor coactivator 4 was decreased, coincident with increased lipid peroxidation and decreased mitochondrial respiration in GFAP-Coasy-derived primary astrocytes. Given that astroglial populations do not fully mature until postnatal weeks 3-4 in mice, deficits in astroglial cells are likely latent and do not fully account for lamination deficits.However, GFAP is also expressed by neural stem cells, thus deletion of CoA synthase may have occurred across all neural cell types, similar to the Nestin-Cre mouse model (Lagace et al., 2007). Regardless, this study suggests subpopulation variability with respect to CoA synthase expression and opens novel insights regarding nucleus-mitochondria crosstalk relevant to age-variant onset Coasy-linked disorders.In the sensory system, Miwa et al. (2025) investigated a global axis between increased substrate consumption of N1-methylnicotinamide (MNAM), a byproduct of NAD + biosynthesis and inhibitor of nicotinamide N-methyltransferase (NNMT), Sirtuin 1 (protein: SIRT1, encoding gene: Sirt1, chr:10), an NAD-dependent transcription factor-deacetylase and effector of NNMT, and their relevance to age-related hearing loss in mouse cochlea. Mice were fed a lowfat diet (LFD) or a low-fat diet with 1% MNAM supplemented from postnatal week 4 and were analyzed for whole body biometrics, auditory brain stem responses, and cochlear metabolomic analysis at 3 months, 6 months, and 12 months of age. The authors report that LFD alone induced steady weight gain over 12 months, whereas LFD + MNAM-fed mice lost significant weight, observable by month 6, although there were no significant changes in blood biomarkers. LFD + MNAM mice also exhibited significant hearing loss by month 6, evident by the increased decibel threshold required to evoke auditory brainstem responses and outer hair cell dysfunction. Histological quantification revealed decreased hair cell number, decreased spiral ganglion cell number, and decreased cochlear turning. Sirt1 protein level was also increased in LFD + MNAM cochlea, and together with the metabolomics analysis of 6-monthold mice, demonstrates notable dysfunction in the metabolic profile by a severe increase in pyruvate compared to the LFD mice. Considered together with previous Sirt1-knockout hearing loss models, this study provides evidence that cochlear physiological function is highly correlated with nuclear-mitochondrial communication, primarily mitigated through Sirt1 signaling axes. Morgan et al. (2024) investigated the effects of a ketogenic diet, typically comprising 70% fat, 20% protein, and 10% carbohydrates, on mitophagy, a selective form of autophagy responsible for eliminating damaged or excess mitochondria. Using mito-qc mice, which express a pH-sensitive mCherry-GFP tag on the outer mitochondrial membrane, the researchers assessed mitophagy by quantifying mitolysosomes in retinal ganglion cells (RGCs) through immunoblotting with RNA Binding Protein with Multiple Splicing (RBPMS).The results revealed a significant increase in mitolysosome numbers in RGCs following ketogenic diet administration, while Müller glia -the principal glial cells in the retina -remained unaffected. Mechanistically, hypoxia triggers mitophagy and that the ketogenic diet serves as an additive enhancer of this process in retinal ganglion cells. The differing response of RGCs and Müller glial cells on ketogenic diet suggesting the variations in their metabolic requirements.In a literature review, Olatona et al. (2025) highlighted the critical role of mitochondria in neurodegeneration of post-traumatic brain injury (TBI), in particular the role of calcium homeostasis, metabolic dysregulation, oxidative stress, and neuroinflammation. The authors postulate that excessive glutamate release during injury results in hyperexcitability, in part due to failure of mechanically stimulated astrocytes to retain and metabolise glutamate. Excess calcium influx results in mitochondrial permeability transition pore (mPTP) formation with elevation of cytosolic calcium, disruption of electron transport chain, and reactive oxygen species production, followed by systemic release upon rupture, including molecular damage associated patterns contributing to neuroinflammation by astrocytes and microglia (e.g. ATP to purinergic receptors, cytochrome C to TLR4 receptors and mtDNA to TLR9 receptors). The interference of mitochondrial respiration persists through the initial response of hyperexcitability and hyper-glycolysis in the first several hours to days followed by hypometabolic phase for weeks, explored in human patients and rodent head impact models. Meanwhile the tissue damage is not restricted to areas of altered bioenergetics. They note similar mechanisms occur in progressive neurodegeneration such as Alzheimer's disease, Parkinson's disease, and motor neuron disease. The authors postulate that targeted therapies to mitochondrial biogenesis such as PGC-1α, or purinergic receptor and STING pathway inhibition may mitigate mitochondrial dysfunction in acute and chronic neurodegeneration. Araujo et al. (2024) investigated the role of astrocytic mitochondrial fragmentation in a cell culture and murine model in age-related decline. They observed that primary senescent astrocytes displayed an increased number of mitochondria, decreased mitochondrial size (MitoTracker) and mitochondrial membrane potential (JC-1). Senescent astrocytes showed increased mitofusin 1 and 2, optic atrophy OPA2, DRP1 and Fis1 gene and protein expression.Young (3-4 months) and aged (over 18 months) mice were used to assess mitochondrial changes in aged astrocytes. In cells isolated from young and old mice, mitochondria were stained using TOMM20 in both astrocytes (GFAP+) and neurons (-Tubulin III) by flow cytometry. Astrocytes and neurons from aged mice showed a decrease in TOMM20 fluorescence intensity. Aged animals show a decline in mitochondrial content in both astrocytes and neurons. Genes that regulated mitochondrial biogenesis, showed a reduction in Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1), Transcription Factor B1, Mitochondrial (TFB1), ATP Synthase F1 Subunit Alpha (ATP5A1) expression. Aged animals exhibit a decline in mitochondrial content in both astrocytes and neurons, as well as decreased expression of genes that regulate mitochondrial biogenesis, and increased DRP1 expression and mitochondrial fission in astrocytes. Astrocytes in aged mice showed a reduction in mitochondrial area, perimeter and a decrease in the number of elongated mitochondria. These data indicate that aging promotes mitochondrial fragmentation in the mammalian brain, impairs energy regulation and highlights a potential imbalance in fission and fusion within senescent cells. Liu et al. (2025) extensively reviewed mitochondrial dysfunction with a focus on mitochondrial quality control processes, in particular biogenesis and mitophagy pathways. The authors highlight further studies could focus on PINK1/Parkin mitophagy validation in vivo, with challenges in specificity and blood-brain barrier permeability currently limiting clinical translation. Controversies persist regarding the exact roles of mitophagy receptors, their impact of mitochondrial dynamics (e.g., Drp1 phosphorylation, OPA1 isoforms). Nonetheless we note the significance of neurodegeneration as proteinopathies remains, in some instances preceded by defective mitochondrial clearance. This is reinforced as the authors summarise that upregulated mitophagy levels can be protective in reducing accumulation of Aβ and hyperphosphorylated tau in Alzheimer's disease, α-syn in Parkinson's disease, mutant Htt in Huntington's disease and SOD1 or TPD-43 early in motor neuron disease progression, although potentially detrimental in latter stages of motor neuron disease. Direct or indirect impaired mitochondrial biogenesis as evident from loss of expression or activity in patient tissue, is thought to contribute to progressive cell death. The authors advise mitochondrial quality control can be further studied with multi-omics, single-cell analysis, and advanced gene technologies, crosstalk between mitochondria and other organelles (e.g., lysosomes, autophagosomes), which contribute to a vicious cycle of dysfunction in neurodegeneration.The studies compiled in this research topic observed various aspects of mitochondrial function in Drosophila, rodent, primary neural and human stem cell platforms, analysing metabolism, mitochondrial biogenesis and mitophagy, neuroinflammation, electrophysiology. On one hand, these studies together reinforce that cross-model eukaryotic observations of mitochondrial dysfunction in neurological function are relatively well conserved. On the other, we note that mitochondrial aetiology may inevitably coincide with any form of cell stress or death, in a way that whole organism deterioration inevitably coincides with loss of respiration. Olatona et al. (2025) advise that brain damage can stem from dysfunction of astrocytic glutamate regulation, resulting in hyperexcitation, mitochondrial failure and rupture with resultant astrocytic and microglial neuroinflammation. As Liu et al. (2025) advise proteinopathies across many major neurodegenerative diseases coincides with defective mitophagy, we further highlight the significance of whole-organelle and protein-nucleic acid complex aggregation, relative to focus on mutation-or stress-induced protein misfolding. The implication of late onset complex cell matter accumulation and neuroinflammation on the approach of precision pharmaceutical research is significant. Furthermore, this reinforces our perspective that simply enhancing mitochondrial respiration is unlikely to greatly improve whole organism survival against cumulative genetic or environmental factors in neurodegeneration as a secondary mitochondrial disease, or aging, and that there may have been disproportionate attention toward oxidative stress or energy regulation that applies more to specific chemical or animal human-like models in the past (Ng et al., 2024).The value of reproducing cytopathology prior to significant apoptotic or necrotic events post-mortem in vitro remains, in absence of real-time human in vivo methods. However, whether current cell culture systems with weekly to monthly timeframes can be effective models of insidious late-onset human neurodegenerative factors for therapeutic treatment, remains to be answered. Further studies may distinguish beyond correlational observations to yield valid causative factors and viable therapeutics, with rigorous testing of converse hypotheses, and appreciation of complexity of cumulative organelle-level aggregation, neuroinflammation and genomic and mitochondrial DNA damage. Incidentally, while our topic indicated the prevalence of animal model platforms for conserved or humanised approaches, along with ethical considerations, we look toward human induced pluripotent stem cell culture models of greater relevance in neurodegeneration and aging.