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Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD + , a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD + biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD + repletion restores NAD + metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD + repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD + levels counteracts WS phenotypes. The molecular mechanisms of mitochondrial dysfunction in the premature ageing Werner syndrome were elusive. Here the authors show that NAD + depletion-induced impaired mitophagy contributes to this phenomenon, shedding light on potential therapeutics.

Decades of research have revealed numerous differences in brain structure size, connectivity and metabolism between males and females. Sex differences in neurobehavioral and cognitive function after various forms of central nervous system (CNS) injury are observed in clinical practice and animal research studies. Sources of sex differences include early life exposure to gonadal hormones, chromosome compliment and adult hormonal modulation. It is becoming increasingly apparent that mitochondrial metabolism and cell death signaling are also sexually dimorphic. Mitochondrial metabolic dysfunction is a common feature of CNS injury. Evidence suggests males predominantly utilize proteins while females predominantly use lipids as a fuel source within mitochondria and that these differences may significantly affect cellular survival following injury. These fundamental biochemical differences have a profound impact on energy production and many cellular processes in health and disease. This review will focus on the accumulated evidence revealing sex differences in mitochondrial function and cellular signaling pathways in the context of CNS injury mechanisms and the potential implications for neuroprotective therapy development.

Neuroendocrine and immune signaling pathways are activated following insults such as stress, injury, and infection, in a systemic response aimed at restoring homeostasis. Mitochondrial metabolism and function have been implicated in the control of immune responses. Commonly studied along with mitochondrial function, reactive oxygen species (ROS) are closely linked to cellular inflammatory responses. It is also accepted that cells experiencing mitochondrial or endoplasmic reticulum (ER) stress induce response pathways in order to cope with protein-folding dysregulation, in homeostatic responses referred to as the unfolded protein responses (UPRs). Recent reports indicate that the UPRs may play an important role in immune responses. Notably, the homeostasis-regulating hormones oxytocin (OXT) and vasopressin (AVP) are also associated with the regulation of inflammatory responses and immune function. Intriguingly, OXT and AVP have been linked with ER unfolded protein responses (UPR ER ), and can impact ROS production and mitochondrial function. Here, we will review the evidence for interactions between these various factors and how these neuropeptides might influence mitochondrial processes.

Alzheimer’s disease (AD) is an incurable neurodegenerative disease that is more prevalent in women. The increased risk of AD in women is not well understood. It is well established that there are sex differences in metabolism and that metabolic alterations are an early component of AD. We utilized a cross-species approach to evaluate conserved metabolic alterations in the serum and brain of human AD subjects, two AD mouse models, a human cell line, and two Caenorhabditis elegans AD strains. We found a mitochondrial complex I-specific impairment in cortical synaptic brain mitochondria in female, but not male, AD mice. In the hippocampus, Polβ haploinsufficiency caused synaptic complex I impairment in male and female mice, demonstrating the critical role of DNA repair in mitochondrial function. In non-synaptic, glial-enriched, mitochondria from the cortex and hippocampus, complex II-dependent respiration increased in female, but not male, AD mice. These results suggested a glial upregulation of fatty acid metabolism to compensate for neuronal glucose hypometabolism in AD. Using an unbiased metabolomics approach, we consistently observed evidence of systemic and brain metabolic remodeling with a shift from glucose to lipid metabolism in humans with AD, and in AD mice. We determined that this metabolic shift is necessary for cellular and organismal survival in C. elegans , and human cell culture AD models. We observed sex-specific, systemic, and brain metabolic alterations in humans with AD, and that these metabolite changes significantly correlate with amyloid and tau pathology. Among the most significant metabolite changes was the accumulation of glucose-6-phosphate in AD, an inhibitor of hexokinase and rate-limiting metabolite for the pentose phosphate pathway (PPP). Overall, we identified novel mechanisms of glycolysis inhibition, PPP, and tricarboxylic acid cycle impairment, and a neuroprotective augmentation of lipid metabolism in AD. These findings support a sex-targeted metabolism-modifying strategy to prevent and treat AD.

Objectives There is a critical need to develop effective treatments for diabetic neuropathy. This study determined if a selective mGluR2/3 receptor agonist prevented or treated experimental diabetic peripheral neuropathy (DPN) through glutamate recycling and improved mitochondrial function. Methods Adult male streptozotocin treated Sprague‐Dawley rats with features of type 1 diabetes mellitus (T1DM) or Low Capacity Running (LCR) rats with insulin resistance or glucose intolerance were treated with 3 or 10 mg/kg/day LY379268. Neuropathy end points included mechanical allodynia, nerve conduction velocities (NCV), and intraepidermal nerve fiber density (IENFD). Markers of oxidative stress, antioxidant response, glutamate recycling pathways, and mitochondrial oxidative phosphorylation (OXPHOS) associated proteins were measured in dorsal root ganglia (DRG). Results In diabetic rats, NCV and IENFD were decreased. Diabetic rats treated with an mGluR2/3 agonist did not develop neuropathy despite remaining diabetic. Diabetic DRG showed increased levels of oxidized proteins, decreased levels of glutathione, decreased levels of mitochondrial DNA (mtDNA) and OXPHOS proteins. In addition, there was a 20‐fold increase in levels of glial fibrillary acidic protein (GFAP) and the levels of glutamine synthetase and glutamate transporter proteins were decreased. When treated with a specific mGluR2/3 agonist, levels of glutathione, GFAP and oxidized proteins were normalized and levels of superoxide dismutase 2 (SOD2), SIRT1, PGC‐1α, TFAM, glutamate transporter proteins, and glutamine synthetase were increased in DRG neurons. Interpretation Activation of glutamate recycling pathways protects diabetic DRG and this is associated with activation of the SIRT1‐PGC‐1α–TFAM axis and preservation of mitochondrial OXPHOS function.

Objectives Diabetes leads to cognitive impairment and is associated with age‐related neurodegenerative diseases including Alzheimer's disease (AD). Thus, understanding diabetes‐induced alterations in brain function is important for developing early interventions for neurodegeneration. Low‐capacity runner (LCR) rats are obese and manifest metabolic risk factors resembling human “impaired glucose tolerance” or metabolic syndrome. We examined hippocampal function in aged LCR rats compared to their high‐capacity runner (HCR) rat counterparts. Methods Hippocampal function was examined using proton magnetic resonance spectroscopy and imaging, unbiased stereology analysis, and a Y maze. Changes in the mitochondrial respiratory chain function and levels of hyperphosphorylated tau and mitochondrial transcriptional regulators were examined. Results The levels of glutamate, myo‐inositol, taurine, and choline‐containing compounds were significantly increased in the aged LCR rats. We observed a significant loss of hippocampal neurons and impaired cognitive function in aged LCR rats. Respiratory chain function and activity were significantly decreased in the aged LCR rats. Hyperphosphorylated tau was accumulated within mitochondria and peroxisome proliferator‐activated receptor‐gamma coactivator 1α, the NAD+‐dependent protein deacetylase sirtuin 1, and mitochondrial transcription factor A were downregulated in the aged LCR rat hippocampus. Interpretation These data provide evidence of a neurodegenerative process in the hippocampus of aged LCR rats, consistent with those seen in aged‐related dementing illnesses such as AD in humans. The metabolic and mitochondrial abnormalities observed in LCR rat hippocampus are similar to well‐described mechanisms that lead to diabetic neuropathy and may provide an important link between cognitive and metabolic dysfunction.

Senescence phenotypes and mitochondrial dysfunction are implicated in aging and in premature aging diseases, including ataxia telangiectasia (A‐T). Loss of mitochondrial function can drive age‐related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence‐associated secretory phenotype (SASP) occur in A‐T patient fibroblasts, and in ATM‐deficient cells and mice. Senescence is mediated by stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide riboside (NR) prevents senescence and SASP by promoting mitophagy in a PINK1‐dependent manner. NR treatment also prevents neurodegeneration, suppresses senescence and neuroinflammation, and improves motor function in Atm−/− mice. Our findings suggest a central role for mitochondrial dysfunction‐induced senescence in A‐T pathogenesis, and that enhancing mitophagy as a potential therapeutic intervention. The underlying cause in most A‐T cases is complex, likely reflecting risks premature aging, multiple genetic factors, and non‐genetic (e.g., environmental, lifestyle/behavioral, and metabolic) factors. These factors can directly/indirectly cause mitophagy defects, leading to accumulation of damaged mitochondria, a major feature of ATM‐deficient animals and A‐T patients. Damaged mitochondria accumulate and release DNA into cytoplasm, which activates STING‐induced glial responses, senescence and SASP. Mitophagy induction by NR treatment maintains a healthy mitochondrial pool and prevents STING activation through efficient clearance of dysfunctional mitochondria and maintains a healthy brain.

Mitochondria contain an autonomous and spatially segregated genome. The organizational unit of their genome is the nucleoid, which consists of mitochondrial DNA (mtDNA) and associated architectural proteins. Here, we show that phase separation is the primary physical mechanism for assembly and size-control of the mitochondrial nucleoid. The major mtDNA-binding protein TFAM spontaneously phase separates in vitro via weak, multivalent interactions into viscoelastic droplets with slow internal dynamics. In combination, TFAM and mtDNA form multiphase, gel-like structures in vitro, which recapitulate the in vivo dynamic behavior of mt-nucleoids. Enlarged, phase-separated, yet transcriptionally active, nucleoids are present in mitochondria from patients with the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS) and are associated with mitochondrial dysfunction. These results point to phase separation as an evolutionarily conserved mechanism of genome organization. Competing Interest Statement The authors have declared no competing interest. Footnotes * Since the last revision, the introduction and discussion sections have been expanded, and panels in figures have been rearranged to span a total of six main figures and six supplementary figures.

Many neurodevelopmental disorders are sex-biased, with males being particularly susceptible to central nervous system (CNS) abnormalities, but mechanisms underlying the sex-biased susceptibility are unclear. Neonatal hypoxic-ischemic encephalopathy (HIE) is one such disorder affecting 1.5-2/1000 live term births that contributes to lifelong cognitive and motor impairments, with males being at a greater risk for these adverse outcomes. Moreover, sex differences in neurobehavioral outcome are observed following the Rice-Vannucci (1981) rodent model of neonatal hypoxic-ischemia (HI). The unilateral carotid artery ligation in this model of HI results in an ipsilateral infarct, and a contralateral “hypoxia-only” hemisphere. Mitochondrial dysfunction is a common feature of CNS injury with increasing evidence suggesting marked sex differences in mitochondrial metabolism of humans and rodents. Following HI, mitochondrial bioenergetic dysfunction contributes to an extended secondary energy failure lasting days or weeks, making it a prime neuroprotective target. Acetyl-L-Carnitine (ALCAR) is neuroprotective following neurotrauma in juvenile and adult animal models; ALCAR is hypothesized to function as an alternative biofuel, antioxidant or by promoting mitochondrial biogenesis but the exact mechanism of neuroprotection is unclear. Emerging evidence suggests that mechanisms implicated in the pathophysiology of CNS injury are also sex dependent including oxidative phosphorylation, oxidative stress, antioxidant defense systems, mitochondrial biogenesis, autophagy and cell death signaling pathways. Therefore, these studies tested the hypotheses that following HIE: mitochondrial function, oxidative stress, antioxidant responses, mitochondrial quality control and cell death are sex dependent, and that ALCAR administration protects against these pathophysiological mechanisms. We observed that complex I mitochondrial respiration is impaired significantly more in males than females, which is associated with increased protein oxidation, impairment of mitochondrial glutathione peroxidase (GPx) activity, and decreased GPx4 immunoreactivity in male, but not female brain. Females have a higher level of reduced glutathione (GSH) than males in shams, decreased GSH, and increased non-mitochondrial GPx activity following HI in both cerebral hemispheres. There is no increase in protein oxidation in the female brain after HI. Furthermore, we find that ALCAR reduces protein oxidation in males following HI. Moreover, we determined mitochondrial fragmentation occurs, to different extents, in both sexes 24 hours after HI. Female mitochondria in the contralateral hemisphere are degraded by mitophagy while male mitochondrial proteins are tagged for removal but the mitophagy machinery is impaired, resulting in an accumulation of damaged mitochondria in the male brain following injury. Finally, we determined that there is significant neuronal cell death in both hemispheres in the male brain following HI, while neuronal death occurs exclusively in the ipsilateral hemisphere of the female brain. These sex-dependent mitochondrial mechanisms further the understanding of a sexually dimorphic neonatal brain injury and will aid in the advancement of sex-specific therapeutic development.