bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒03‒13
nineteen papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico

  1. Anal Biochem. 2022 Mar 05. pii: S0003-2697(22)00102-6. [Epub ahead of print] 114646
      Mitochondrial complex I is the only enzyme responsible for oxidation of matrix NADH and regeneration of NAD+ for catabolism. Nuclear and mtDNA mutations, assembly impairments, and enzyme damage are implicated in inherited diseases, ischemia-reperfusion injury, neurodegeneration, and tumorogenesis. Here we introduce a novel method to measure the absolute content of complex I. The method is based on flavin fluorescence scanning of a polyacrylamide gel after separation of complexes by Clear Native electrophoresis. Using mouse primary astrocytes as an example, we calculated an average value of 2.2 × 105 complex I molecules/cell. Our method can be used for accurate quantification of complex I content.
    Keywords:  Astrocytes; Flavin mononucleotide; Fluorescence; Mitochondrial complex I; Respiratory chain
  2. Neurol Genet. 2022 Apr;8(2): e660
      Background and Objectives: We report the pathogenic sequence variant m.5789T>C in the anticodon stem of the mitochondrial tRNA for cysteine as a novel cause of neuropathy, ataxia, and retinitis pigmentosa (NARP), which is usually associated with pathogenic variants in the MT-ATP6 gene.Methods: To address the correlation of oxidative phosphorylation deficiency with mutation loads, we performed genotyping on single laser-dissected skeletal muscle fibers. Stability of the mitochondrial tRNACys was investigated by Northern blotting. Accompanying deletions of the mitochondrial genome were detected by long-range PCR and their breakpoints were determined by sequencing of single-molecule amplicons.
    Results: The sequence variant m.5789T>C, originating from the patient's mother, decreases the stability of the mitochondrial tRNA for cysteine by disrupting the anticodon stem, which subsequently leads to a combined oxidative phosphorylation deficiency. In parallel, we observed a prominent cluster of low-abundance somatic deletions with breakpoints in the immediate vicinity of the m.5789T>C variant. Strikingly, all deletion-carrying mitochondrial DNA (mtDNA) species, in which the corresponding nucleotide position was not removed, harbored the mutant allele, and none carried the wild-type allele.
    Discussion: In addition to providing evidence for the novel association of a tRNA sequence alteration with NARP syndrome, our observations support the hypothesis that single nucleotide changes can lead to increased occurrence of site-specific mtDNA deletions through the formation of an imperfect repeat. This finding might be relevant for understanding mechanisms of deletion generation in the human mitochondrial genome.
  3. Cell Rep. 2022 Mar 08. pii: S2211-1247(22)00208-X. [Epub ahead of print]38(10): 110475
      Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knockin mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses, leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt.
    Keywords:  1C metabolism; CHCHD10; coiled-coil-helix-coiled-coil-helix domain containing 10; heart, cardiomyopathy; heme; integrated stress response; metabolic rewiring; mitochondria
  4. Acta Pharm Sin B. 2022 Feb;12(2): 483-495
      Alzheimer's disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.
    Keywords:  AD, Alzheimer's disease; ADP, adenosine diphosphate; AIDS, acquired immunodeficiency syndrome; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; APP/PS1, amyloid precursor protein/presenilin 1; ATP, adenosine triphosphate; Alzheimer's disease; Aβ, amyloid beta; BBB, blood‒brain barrier; BDNF, brain-derived neurotrophic factor; CP2, tricyclic pyrone compound two; Complex I inhibitors; ER, endoplasmic reticulum; ETC, electron transport chain; FADH2, flavin adenine dinucleotide; FDG-PET, fluorodeoxyglucose-positron emission tomography; GWAS, genome-wide association study; HD, Huntington's disease; HIF-1α, hypoxia induced factor 1 α; Healthy aging; ISR, integrated stress response; Integrated stress response; LTP, long term potentiation; MCI, mild cognitive impairment; MPTP, 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine; Mitochondria; Mitochondria signaling; Mitochondria targeted therapeutics; NAD+ and NADH, nicotinamide adenine dinucleotide; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRF2, nuclear factor E2-related factor 2; Neuroprotection; OXPHOS, oxidative phosphorylation; PD, Parkinson's disease; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PMF, proton-motive force; RNAi, RNA interference; ROS, reactive oxygen species; T2DM, type II diabetes mellitus; TCA, the tricarboxylic acid cycle; mtDNA, mitochondrial DNA; mtUPR, mitochondrial unfolded protein response; pTau, hyper-phosphorylated Tau protein; ΔpH, proton gradient; Δψm, mitochondrial membrane potential
  5. Front Cell Dev Biol. 2022 ;10 781558
      Mitochondria are biosynthetic, bioenergetic, and signaling organelles with a critical role in cellular physiology. Dysfunctional mitochondria are associated with aging and underlie the cause of a wide range of diseases, from neurodegeneration to cancer. Through signaling, mitochondria regulate diverse biological outcomes. The maintenance of the mitochondrial membrane potential, for instance, is essential for proliferation, the release of mitochondrial reactive oxygen species, and oxygen sensing. The loss of mitochondrial membrane potential triggers pathways to clear damaged mitochondria and often results in cell death. In this study, we conducted a genome-wide positive selection CRISPR screen using a combination of mitochondrial inhibitors to uncover genes involved in sustaining a mitochondrial membrane potential, and therefore avoid cell death when the electron transport chain is impaired. Our screen identified genes involved in mitochondrial protein translation and ATP synthesis as essential for the induction of cell death when cells lose their mitochondrial membrane potential. This report intends to provide potential targets for the treatment of diseases associated with mitochondrial dysfunction.
    Keywords:  ATP synthase; CRISPR screen; cell death; mitochondria; mitochondrial membrane potential; mitochondrial protein translation
  6. J Biol Chem. 2022 Mar 02. pii: S0021-9258(22)00231-9. [Epub ahead of print] 101791
      Many proteins are modified by post-translational methylation, introduced by a number of methyltransferases (MTases). Protein methylation plays important roles in modulating protein function, and thus in optimizing and regulating cellular and physiological processes. Research has mainly focused on nuclear and cytosolic protein methylation, but it has been known for many years that also mitochondrial proteins are methylated. During the last decade, significant progress has been made on identifying the MTases responsible for mitochondrial protein methylation and addressing its functional significance. In particular, several novel human MTases have been uncovered that methylate lysine, arginine, histidine, and glutamine residues in various mitochondrial substrates. Several of these substrates are key components of the bioenergetics machinery, e.g. respiratory Complex I, citrate synthase and the ATP synthase. In the present review we report the status of the field of mitochondrial protein methylation, with a particular emphasis on recently discovered human MTases. We also discuss evolutionary aspects and functional significance of mitochondrial protein methylation, and present an outlook for this emergent research field.
    Keywords:  ATP synthase; bioenergetics; electron transport chain; methyltransferase; mitochondria; oxidative phosphorylation; protein methylation
  7. Front Aging. 2022 ;pii: 805126. [Epub ahead of print]2
      Mitochondria are the main source of energy used to maintain cellular homeostasis. This aspect of mitochondrial biology underlies their putative role in age-associated tissue dysfunction. Proper functioning of the electron transport chain (ETC), which is partially encoded by the extra-nuclear mitochondrial genome (mtDNA), is key to maintaining this energy production. The acquisition of de novo somatic mutations that interrupt the function of the ETC have long been associated with aging and common diseases of the elderly. Yet, despite over 30 years of study, the exact role(s) mtDNA mutations play in driving aging and its associated pathologies remains under considerable debate. Furthermore, even fundamental aspects of age-related mtDNA mutagenesis, such as when mutations arise during aging, where and how often they occur across tissues, and the specific mechanisms that give rise to them, remain poorly understood. In this review, we address the current understanding of the somatic mtDNA mutations, with an emphasis of when, where, and how these mutations arise during aging. Additionally, we highlight current limitations in our knowledge and critically evaluate the controversies stemming from these limitations. Lastly, we highlight new and emerging technologies that offer potential ways forward in increasing our understanding of somatic mtDNA mutagenesis in the aging process.
    Keywords:  aging; mitochondria; mtDNA; mutagenesis; sequencing; somatic mutations
  8. Acta Pharm Sin B. 2022 Feb;12(2): 511-531
      Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.
    Keywords:  ACE2, angiotensin I converting enzyme (peptidyl-dipeptidase A) 2; AD, Alzheimer's disease; ADP, adenosine diphosphate; ADRD, AD-related dementias; Aβ, amyloid β; CSF, cerebrospinal fluid; Circadian regulation; DAMPs; DAMPs, damage-associated molecular patterns; Diabetes; ER, estrogen receptor; ETC, electron transport chain; FCCP, trifluoromethoxy carbonylcyanide phenylhydrazone; FPR-1, formyl peptide receptor 1; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HBP, hexoamine biosynthesis pathway; HTRA, high temperature requirement A; Hexokinase biosynthesis pathway; I3A, indole-3-carboxaldehyde; IRF-3, interferon regulatory factor 3; LC3, microtubule associated protein light chain 3; LPS, lipopolysaccharide; LRR, leucine-rich repeat; MAVS, mitochondrial anti-viral signaling; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; Mdivi-1, mitochondrial division inhibitor 1; Microbiome; Mitochondrial DNA; Mitochondrial electron transport chain; Mitochondrial quality control; NLRP3, leucine-rich repeat (LRR)-containing protein (NLR)-like receptor family pyrin domain containing 3; NOD, nucleotide-binding oligomerization domain; NeuN, neuronal nuclear protein; PET, fluorodeoxyglucose (FDG)-positron emission tomography; PKA, protein kinase A; POLβ, the base-excision repair enzyme DNA polymerase β; ROS, reactive oxygen species; Reactive species; SAMP8, senescence-accelerated mice; SCFAs, short-chain fatty acids; SIRT3, NAD-dependent deacetylase sirtuin-3; STING, stimulator of interferon genes; STZ, streptozotocin; SkQ1, plastoquinonyldecyltriphenylphosphonium; T2D, type 2 diabetes; TCA, Tricarboxylic acid; TLR9, toll-like receptor 9; TMAO, trimethylamine N-oxide; TP, tricyclic pyrone; TRF, time-restricted feeding; cAMP, cyclic adenosine monophosphate; cGAS, cyclic GMP/AMP synthase; hAPP, human amyloid precursor protein; hPREP, human presequence protease; i.p., intraperitoneal; mTOR, mechanistic target of rapamycin; mtDNA, mitochondrial DNA; αkG, alpha-ketoglutarate
  9. Int J Mol Sci. 2022 Feb 28. pii: 2717. [Epub ahead of print]23(5):
      Mitochondria control cellular fate by various mechanisms and are key drivers of cellular metabolism. Although the main function of mitochondria is energy production, they are also involved in cellular detoxification, cellular stabilization, as well as control of ketogenesis and glucogenesis. Conditions like neurodegenerative disease, insulin resistance, endocrine imbalances, liver and kidney disease are intimately linked to metabolic disorders or inflexibility and to mitochondrial dysfunction. Mitochondrial dysfunction due to a relative lack of micronutrients and substrates is implicated in the development of many chronic diseases. l-carnitine is one of the key nutrients for proper mitochondrial function and is notable for its role in fatty acid oxidation. l-carnitine also plays a major part in protecting cellular membranes, preventing fatty acid accumulation, modulating ketogenesis and glucogenesis and in the elimination of toxic metabolites. l-carnitine deficiency has been observed in many diseases including organic acidurias, inborn errors of metabolism, endocrine imbalances, liver and kidney disease. The protective effects of micronutrients targeting mitochondria hold considerable promise for the management of age and metabolic related diseases. Preventing nutrient deficiencies like l-carnitine can be beneficial in maintaining metabolic flexibility via the optimization of mitochondrial function. This paper reviews the critical role of l-carnitine in mitochondrial function, metabolic flexibility and in other pathophysiological cellular mechanisms.
    Keywords:  beta oxidation; diabetes; fatty acid oxidation; glycolysis; ketogenesis; l-carnitine; liver disease; metabolic inflexibility; mitochondrial function; neurodegeneration
  10. Aging Cell. 2022 Mar 09. e13583
      Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria (MIT) in muscle could trigger inflammation in the context of aging is still unknown. Here, we demonstrate that BCL2 interacting protein 3 (BNIP3) plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of Toll-like receptor 9 (TLR9)-dependent inflammation and activation of the NLRP3 (nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3) inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans. Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.
    Keywords:  aging; inflammation; lysosome; mitochondria; mitophagy; muscle
  11. Front Cell Dev Biol. 2022 ;10 826981
      Skeletal muscle fibers contain a large number of mitochondria, which produce ATP through oxidative phosphorylation (OXPHOS) and provide energy for muscle contraction. In this process, mitochondria also produce several types of "reactive species" as side product, such as reactive oxygen species and reactive nitrogen species which have attracted interest. Mitochondria have been proven to have an essential role in the production of skeletal muscle reactive oxygen/nitrogen species (RONS). Traditionally, the elevation in RONS production is related to oxidative stress, leading to impaired skeletal muscle contractility and muscle atrophy. However, recent studies have shown that the optimal RONS level under the action of antioxidants is a critical physiological signal in skeletal muscle. Here, we will review the origin and physiological functions of RONS, mitochondrial structure and function, mitochondrial dynamics, and the coupling between RONS and mitochondrial oxidative stress. The crosstalk mechanism between mitochondrial function and RONS in skeletal muscle and its regulation of muscle stem cell fate and myogenesis will also be discussed. In all, this review aims to describe a comprehensive and systematic network for the interaction between skeletal muscle mitochondrial function and RONS.
    Keywords:  RONS; mitochondrial dynamics; mitochondrial function; oxidative stress; skeletal muscle
  12. PLoS One. 2022 ;17(3): e0265141
      PURPOSE: Muscle biopsies are the gold standard to assess mitochondrial respiration; however, biopsies are not always a feasible approach in persons with spinal cord injury (SCI). Peripheral blood mononuclear cells (PBMCs) and near-infrared spectroscopy (NIRS) may alternatively be predictive of mitochondrial respiration. The purpose of the study was to evaluate whether mitochondrial respiration of PBMCs and NIRS are predictive of respiration of permeabilized muscle fibers after SCI.METHODS: Twenty-two individuals with chronic complete and incomplete motor SCI between 18-65 years old were recruited to participate in the current trial. Using high-resolution respirometry, mitochondrial respiratory capacity was measured for PBMCs and muscle fibers of the vastus lateralis oxidizing complex I, II, and IV substrates. NIRS was used to assess mitochondrial capacity of the vastus lateralis with serial cuff occlusions and electrical stimulation.
    RESULTS: Positive relationships were observed between PBMC and permeabilized muscle fibers for mitochondrial complex IV (r = 0.86, P < 0.0001). Bland-Altman displayed agreement for complex IV (MD = 0.18, LOA = -0.86 to 1.21), between PBMCs and permeabilized muscles fibers. No significant relationships were observed between NIRS mitochondrial capacity and respiration in permeabilized muscle fibers.
    CONCLUSIONS: This is the first study to explore and support the agreement of less invasive clinical techniques for assessing mitochondrial respiratory capacity in individuals with SCI. The findings will assist in the application of PBMCs as a viable alternative for assessing mitochondrial health in persons with SCI in future clinical studies.
  13. Int J Mol Sci. 2022 Mar 07. pii: 2888. [Epub ahead of print]23(5):
      Molecular hydrogen ameliorates pathological states in a variety of human diseases, animal models, and cell models, but the effects of hydrogen on cancer have been rarely reported. In addition, the molecular mechanisms underlying the effects of hydrogen remain mostly unelucidated. We found that hydrogen enhances proliferation of four out of seven human cancer cell lines (the responders). The proliferation-promoting effects were not correlated with basal levels of cellular reactive oxygen species. Expression profiling of the seven cells showed that the responders have higher gene expression of mitochondrial electron transport chain (ETC) molecules than the non-responders. In addition, the responders have higher mitochondrial mass, higher mitochondrial superoxide, higher mitochondrial membrane potential, and higher mitochondrial spare respiratory capacity than the non-responders. In the responders, hydrogen provoked mitochondrial unfolded protein response (mtUPR). Suppression of cell proliferation by rotenone, an inhibitor of mitochondrial ETC complex I, was rescued by hydrogen in the responders. Hydrogen triggers mtUPR and induces cell proliferation in cancer cells that have high basal and spare mitochondrial ETC activities.
    Keywords:  cancer cell lines; cellular proliferation; mitochondrial electron transfer chain; mitochondrial unfolded protein response; molecular hydrogen
  14. Sci Rep. 2022 Mar 10. 12(1): 4222
      Recent scientific evidence suggests a link between migraine and brain energy metabolism. In fact, migraine is frequently observed in mitochondrial disorders. We studied 46 patients affected by mitochondrial disorders, through a headache-focused semi-structured interview, to evaluate the prevalence of migraine among patients affected by mitochondrial disorders, the possible correlations between migraine and neuromuscular genotype or phenotype, comorbidities, lactate acid levels and brain magnetic resonance spectroscopy. We explored migraine-related disability, analgesic and prophylactic treatments. Diagnoses were achieved according to International Classification of Headache Disorders, 3rd edition. Lifetime prevalence of migraine was 61% (28/46), with high values in both sexes (68% in females, 52% in males) and higher than the values found in both the general population and previous literature. A maternal inheritance pattern was reported in 57% of cases. MIDAS and HIT6 scores revealed a mild migraine-related disability. The high prevalence of migraine across different neuromuscular phenotypes and genotypes suggests that migraine itself may be a common clinical manifestation of brain energy dysfunction. Our results provide new relevant indications in favour of migraine as the result of brain energy unbalance.
  15. Theranostics. 2022 ;12(5): 2445-2464
      Organelles are tiny structures with specific functions in eukaryotic cells. Since they are covered with membranes, different organelles can perform biological processes that are incompatible. Organelles can also actively communicate with each other to maintain cellular homeostasis via the vesicular trafficking pathways and membrane contact sites (MCSs), which allow the exchange of metabolites and other information required for normal cellular physiology. An imbalance in organelle interactions may result in multiple pathological processes. Growing evidence shows that abnormal organelle communication contributes to cellular senescence and is associated with organ aging. However, the key role of organelle interactions in aging has not yet been broadly reviewed and fully investigated. In this review, we summarize the role of organelle interactions in cellular senescence, and highlight their relevance for cellular calcium homeostasis, protein and lipid homeostasis, and mitochondrial quality control. Our review reveals important mechanisms of organelle interactions in cellular senescence and provides important clues for intervention strategies from a new perspective.
    Keywords:  MCSs; cellular senescence; communication; interaction; organelle
  16. Sci Rep. 2022 Mar 08. 12(1): 4056
      Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how these factors affect placental function. We investigated how mitochondrial dysfunction and high hCG expression affected placental function in unexplained FGR and PE/FGR. We observed elevated expression of hCGβ and growth differentiation factor 15 mRNA and protein levels in the placenta with both diseases. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα, were also upregulated at the mRNA level. In addition, the expression of COXI and COXII which encoded by mitochondrial DNA were significantly decreased in both diseases, suggesting that mitochondrial translation was impaired. Treatment with hCG increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via the p38 and JNK pathways. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression. These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR.
  17. Mol Neurobiol. 2022 Mar 09.
      Ischemic stroke is a cerebrovascular disease with high mortality and disability, which seriously affects the health and lives of people around the world. Effective treatment for ischemic stroke has been limited by its complex pathological mechanisms. Increasing evidence has indicated that mitochondrial dysfunction plays an essential role in the occurrence, development, and pathological processes of ischemic stroke. Therefore, strict control of the quality and quantity of mitochondria via mitochondrial fission and fusion as well as mitophagy is beneficial to the survival and normal function maintenance of neurons. Under certain circumstances, excessive mitophagy also could induce cell death. This review discusses the dynamic changes and double-edged roles of mitochondria and related signaling pathways of mitophagy in the pathophysiology of ischemic stroke. Furthermore, we focus on the possibility of modulating mitophagy as a potential therapy for the prevention and prognosis of ischemic stroke. Notably, we reviewed recent advances in the studies of natural compounds, which could modulate mitophagy and exhibit neuroprotective effects, and discussed their potential application in the treatment of ischemic stroke.
    Keywords:  Ischemic stroke; Mitochondria; Mitochondrial dynamics; Mitophagy
  18. Curr Aging Sci. 2022 Mar 04.
      Sarcopenia is an emerging clinical entity characterized by a gradual decline in skeletal muscle mass and strength that accompanies the normal aging process. It has been noted that sarcopenia is associated with various adverse health outcomes in the geriatric population like prolonged hospital admission, disability, poor quality of life, frailty, and mortality. Factors involved in the development of age-related sarcopenia include anorexia, alteration in the hormone levels, decreased neural innervation, low blood flow to the muscles, cytokine dysregulation, altered mitochondrial activity, genomic instability, intracellular proteolysis, and insulin resistance. Understanding the mechanism may help develop efficient preventive and therapeutic strategies which can improve the quality of life in elderly individuals. Thus, the objective of the present article is to review the literature regarding the mechanism involved in the development of sarcopenia in aged individuals.
    Keywords:  Sarcopenia; aging; anorexia; frailty; insulin resistance; skeletal muscle
  19. Sci Rep. 2022 Mar 11. 12(1): 4287
      Mitochondrial defects result in dysregulation of metabolomics and energy homeostasis that are detected in upper motor neurons (UMNs) with TDP-43 pathology, a pathology that is predominantly present in both familial and sporadic cases of amyotrophic lateral sclerosis (ALS). While same mitochondrial problems are present in the UMNs of ALS patients with TDP-43 pathology and UMNs of TDP-43 mouse models, and since pathologies are shared at a cellular level, regardless of species, we first analyzed the metabolite profile of both healthy and diseased motor cortex to investigate whether metabolomic changes occur with respect to TDP-43 pathology. High-performance liquid chromatography, high-resolution mass spectrometry and tandem mass spectrometry (HPLC-MS/MS) for metabolite profiling began to suggest that reduced levels of NAD+ is one of the underlying causes of metabolomic problems. Since nicotinamide mononucleotide (NMN) was reported to restore NAD+ levels, we next investigated whether NMN treatment would improve the health of diseased corticospinal motor neurons (CSMN, a.k.a. UMN in mice). prpTDP-43A315T-UeGFP mice, the CSMN reporter line with TDP-43 pathology, allowed cell-type specific responses of CSMN to NMN treatment to be assessed in vitro. Our results show that metabolomic defects occur early in ALS motor cortex and establishing NAD+ balance could offer therapeutic benefit to UMNs with TDP-43 pathology.