bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒10‒30
thirty-one papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico

  1. EMBO J. 2022 Oct 28. e110595
      Mammalian SWI/SNF/BAF chromatin remodeling complexes influence cell lineage determination. While the contribution of these complexes to neural progenitor cell (NPC) proliferation and differentiation has been reported, little is known about the transcriptional profiles that determine neurogenesis or gliogenesis. Here, we report that BCL7A is a modulator of the SWI/SNF/BAF complex that stimulates the genome-wide occupancy of the ATPase subunit BRG1. We demonstrate that BCL7A is dispensable for SWI/SNF/BAF complex integrity, whereas it is essential to regulate Notch/Wnt pathway signaling and mitochondrial bioenergetics in differentiating NPCs. Pharmacological stimulation of Wnt signaling restores mitochondrial respiration and attenuates the defective neurogenic patterns observed in NPCs lacking BCL7A. Consistently, treatment with an enhancer of mitochondrial biogenesis, pioglitazone, partially restores mitochondrial respiration and stimulates neuronal differentiation of BCL7A-deficient NPCs. Using conditional BCL7A knockout mice, we reveal that BCL7A expression in NPCs and postmitotic neurons is required for neuronal plasticity and supports behavioral and cognitive performance. Together, our findings define the specific contribution of BCL7A-containing SWI/SNF/BAF complexes to mitochondria-driven NPC commitment, thereby providing a better understanding of the cell-intrinsic transcriptional processes that connect metabolism, neuronal morphogenesis, and cognitive flexibility.
    Keywords:  BCL7A; SWI/SNF/BAF complex; cognitive function; mitochondrial OXPHOS; neural progenitor cells (NPCs)
  2. Biomedicines. 2022 Oct 12. pii: 2539. [Epub ahead of print]10(10):
      Mitochondria are essential organelles and crucial for cellular survival. Mitochondrial biogenesis and mitophagy are dynamic features that are essential for both maintaining the health of the mitochondrial network and cellular demands. The accumulation of damaged mitochondria has been shown to be related to a wide range of pathologies ranging from neurological to musculoskeletal. Mitophagy is the selective autophagy of mitochondria, eliminating dysfunctional mitochondria in cells by engulfment within double-membraned vesicles. Preeclampsia and low birth weight constitute prenatal complications during pregnancy and are leading causes of maternal and fetal mortality and morbidity. Both placental implantation and fetal growth require a large amount of energy, and a defect in the mitochondrial quality control mechanism may be responsible for the pathophysiology of these diseases. In this review, we compiled current studies investigating the role of BNIP3, DRAM1, and FUNDC1, mediators of receptor-mediated mitophagy, in the progression of preeclampsia and the role of mitophagy pathways in the pathophysiology of low birth weight. Recent studies have indicated that mitochondrial dysfunction and accumulation of reactive oxygen species are related to preeclampsia and low birth weight. However, due to the lack of studies in this field, the results are controversial. Therefore, mitophagy-related pathways associated with these pathologies still need to be elucidated. Mitophagy-related pathways are among the promising study targets that can reveal the pathophysiology behind preeclampsia and low birth weight.
    Keywords:  fetal growth restriction; low birth weight; mitochondria; mitophagy; perinatal complications; preeclampsia
  3. Cell Death Differ. 2022 Oct 28.
      Macrophages are essential players for the host response against pathogens, regulation of inflammation and tissue regeneration. The wide range of macrophage functions rely on their heterogeneity and plasticity that enable a dynamic adaptation of their responses according to the surrounding environmental cues. Recent studies suggest that metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the metabolic pathways orchestrating macrophage activation are still under scrutiny. Optic atrophy 1 (OPA1) is a mitochondria-shaping protein controlling mitochondrial fusion, cristae biogenesis and respiration; clear evidence shows that the lack or dysfunctional activity of this protein triggers the accumulation of metabolic intermediates of the TCA cycle. In this study, we show that OPA1 has a crucial role in macrophage activation. Selective Opa1 deletion in myeloid cells impairs M1-macrophage commitment. Mechanistically, Opa1 deletion leads to TCA cycle metabolite accumulation and defective NF-κB signaling activation. In an in vivo model of muscle regeneration upon injury, Opa1 knockout macrophages persist within the damaged tissue, leading to excess collagen deposition and impairment in muscle regeneration. Collectively, our data indicate that OPA1 is a key metabolic driver of macrophage functions.
  4. Int J Mol Sci. 2022 Oct 20. pii: 12610. [Epub ahead of print]23(20):
      The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that stimulate mitochondrial biogenesis to boost ATP production. Here, we examined the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in Short chain enoyl-CoA hydratase 1 (ECHS1) 'knockout' (KO) cells, which exhibit combined defects in both oxidative phosphorylation (OXPHOS) and mitochondrial fatty acid β-oxidation (FAO). DNs treatment increased mitochondrial DNA (mtDNA) copy number and the expression of mtDNA-encoded transcripts in both CONTROL (CON) and ECHS1 KO cells. DNs treatment also altered global nuclear gene expression, with key gene sets including 'respiratory electron transport' and 'formation of ATP by chemiosmotic coupling' increased in both CON and ECHS1 KO cells. Genes involved in OXPHOS complex I biogenesis were also upregulated in both CON and ECHS1 KO cells following dNs treatment, with a corresponding increase in the steady-state levels of holocomplex I in ECHS1 KO cells. Steady-state levels of OXPHOS complex V, and the CIII2/CIV and CI/CIII2/CIV supercomplexes, were also increased by dNs treatment in ECHS1 KO cells. Importantly, treatment with dNs increased both basal and maximal mitochondrial oxygen consumption in ECHS1 KO cells when metabolizing either glucose or the fatty acid palmitoyl-L-carnitine. These findings highlight the ability of dNs to improve overall mitochondrial respiratory function, via the stimulation mitochondrial biogenesis, in the face of combined defects in OXPHOS and FAO due to ECHS1 deficiency.
    Keywords:  ECHS1 deficiency; deoxyribonucleosides; mitochondria; mitochondrial biogenesis; mitochondrial disease
  5. HGG Adv. 2023 Jan 12. 4(1): 100148
      Mitochondrial diseases are a heterogeneous group of genetic disorders caused by pathogenic variants in genes encoding gene products that regulate mitochondrial function. These genes are located either in the mitochondrial or in the nuclear genome. The TOMM7 gene encodes a regulatory subunit of the translocase of outer mitochondrial membrane (TOM) complex that plays an essential role in translocation of nuclear-encoded mitochondrial proteins into mitochondria. We report an individual with a homozygous variant in TOMM7 (c.73T>C, p.Trp25Arg) that presented with a syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. Analysis of mouse models strongly suggested that the identified variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with homozygous Tomm7 deletion. These Tomm7 mutant mice show pathological changes consistent with mitochondrial dysfunction, including growth defects, severe lipoatrophy, and lipid accumulation in the liver. These mice die prematurely following a rapidly progressive weight loss during the last week of their lives. Tomm7 deficiency causes a unique alteration in mitochondrial function; despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis without impairing the function of the tricarboxylic cycle metabolism or ETC. This study presents evidence that a hypomorphic variant in one of the genes encoding a subunit of the TOM complex causes mitochondrial disease.
    Keywords:  TOM; TOMM7; developmental delay; fatty liver; growth plate; lipoatrophy; mitochondria; mouse model; skeletal dysplasia; translocase
  6. Front Cell Dev Biol. 2022 ;10 978142
      Aging is characterised by the progressive accumulation of cellular dysfunction, stress, and inflammation. A large body of evidence implicates mitochondrial dysfunction as a cause or consequence of age-related diseases including metabolic disorders, neuropathies, various forms of cancer and neurodegenerative diseases. Because neurons have high metabolic demands and cannot divide, they are especially vulnerable to mitochondrial dysfunction which promotes cell dysfunction and cytotoxicity. Mitophagy neutralises mitochondrial dysfunction, providing an adaptive quality control strategy that sustains metabolic homeostasis. Mitophagy has been extensively studied as an inducible stress response in cultured cells and short-lived model organisms. In contrast, our understanding of physiological mitophagy in mammalian aging remains extremely limited, particularly in the nervous system. The recent profiling of mitophagy reporter mice has revealed variegated vistas of steady-state mitochondrial destruction across different tissues. The discovery of patients with congenital autophagy deficiency provokes further intrigue into the mechanisms that underpin neural integrity. These dimensions have considerable implications for targeting mitophagy and other degradative pathways in age-related neurological disease.
    Keywords:  aging; autophagy; brain; disease; longevity; mitochondria; mitophagy
  7. Nutrients. 2022 Oct 16. pii: 4326. [Epub ahead of print]14(20):
      Mitochondria participate in the maintenance of cellular homeostasis. Firstly, mitochondria regulate energy metabolism through oxidative phosphorylation. In addition, they are involved in cell fate decisions by activating the apoptotic intrinsic pathway. Finally, they work as intracellular signaling hubs as a result of their tight regulation of ion and metabolite concentrations and other critical signaling molecules such as ROS. Aging is a multifactorial process triggered by impairments in different cellular components. Among the various molecular pathways involved, mitochondria are key regulators of longevity. Indeed, mitochondrial deterioration is a critical signature of the aging process. In this scenario, we will focus specifically on the age-related decrease in CoQ levels, an essential component of the electron transport chain (ETC) and an antioxidant, and how CoQ supplementation could benefit the aging process. Generally, any treatment that improves and sustains mitochondrial functionality is a good candidate to counteract age-related mitochondrial dysfunctions. In recent years, heightened attention has been given to natural compounds that modulate mitochondrial function. One of the most famous is resveratrol due to its ability to increase mitochondrial biogenesis and work as an antioxidant agent. This review will discuss recent clinical trials and meta-analyses based on resveratrol and CoQ supplementation, focusing on how these compounds could improve mitochondrial functionality during aging.
    Keywords:  aging; coenzymeQ10; mitochondria; resveratrol
  8. Front Genet. 2022 ;13 951185
      The mitochondrial DNA (mtDNA) m.3243A>G mutation is one of the most common pathogenic mtDNA variants, showing complex genetics, pathogenic molecular mechanisms, and phenotypes. In recent years, the prevention of mtDNA-related diseases has trended toward precision medicine strategies, such as preimplantation genetic diagnosis (PGD) and mitochondrial replacement therapy (MRT). These techniques are set to allow the birth of healthy children, but clinical implementation relies on thorough insights into mtDNA genetics. The genotype and phenotype of m.3243A>G vary greatly from mother to offspring, which compromises genetic counseling for the disease. This review is the first to systematically elaborate on the characteristics of the m.3243A>G mutation, from genetics to phenotype and the relationship between them, as well as the related influencing factors and potential strategies for preventing disease. These perceptions will provide clarity for clinicians providing genetic counseling to m.3243A>G patients.
    Keywords:  fertility counseling; genetics; heteroplasmy; m.3243A>G; phenotype
  9. J Clin Invest. 2022 Oct 26. pii: e161566. [Epub ahead of print]
      Charcot-Marie-Tooth disease (CMT) type 2A is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying axonal pathology is unknown. SARM1, the central executioner of axon degeneration, can induce neuropathy and is activated by dysfunctional mitochondria. We tested the role of SARM1 in a rat model carrying a dominant CMT2A mutation (Mfn2H361Y) that exhibits progressive dying-back axonal degeneration, NMJ abnormalities, muscle atrophy, and mitochondrial abnormalities, all hallmarks of the human disease. We generated Sarm1 knockout and Mfn2H361Y, Sarm1 double mutant rats and find that deletion of Sarm1 rescues axonal, synaptic, muscle, and functional phenotypes, demonstrating that SARM1 is responsible for much of the neuropathology in this model. Despite the presence of mutant MFN2 protein in these double mutant rats, loss of SARM1 also dramatically suppressed many mitochondrial defects, including the number, size, and cristae density defects of synaptic mitochondria. This surprising finding indicates that dysfunctional mitochondria activate SARM1, and activated SARM1 feeds back on mitochondria to exacerbate mitochondrial pathology. As such, this work identifies SARM1 inhibition as an exciting therapeutic candidate for the treatment of CMT2A and other neurodegenerative diseases with prominent mitochondrial pathology.
    Keywords:  Neurodegeneration; Neurological disorders; Neuromuscular disease; Neuroscience
  10. Metabolites. 2022 Oct 08. pii: 955. [Epub ahead of print]12(10):
      COQ8A-ataxia is a mitochondrial disease in which a defect in coenzyme Q10 synthesis leads to dysfunction of the respiratory chain. The disease is usually present as childhood-onset progressive ataxia with developmental regression and cerebellar atrophy. However, due to variable phenotype, it may be hard to distinguish from other mitochondrial diseases and a wide spectrum of childhood-onset cerebellar ataxia. COQ8A-ataxia is a potentially treatable condition with the supplementation of coenzyme Q10 as a main therapy; however, even 50% may not respond to the treatment. In this study we review the clinical manifestation and management of COQ8A-ataxia, focusing on current knowledge of coenzyme Q10 supplementation and approach to further therapies. Moreover, the case of a 22-month-old girl with cerebellar ataxia and developmental regression will be presented.
    Keywords:  COQ8A; COQ8A-ataxia; cerebellar ataxia; coenzyme Q10; primary coenzyme Q10 deficiency; primary coenzyme Q10 deficiency-4
  11. Trends Cell Biol. 2022 Oct 19. pii: S0962-8924(22)00230-6. [Epub ahead of print]
      Brown adipose tissue (BAT) controls mammalian core body temperature by non-shivering thermogenesis. BAT is extraordinarily rich in mitochondria, which have the peculiarity of generating heat by uncoupled respiration. Since the mitochondrial activity of BAT is subject to cycles of activation and deactivation in response to environmental temperature changes, an integrated mitochondrial quality control (MQC) system is of fundamental importance to ensure BAT physiology. Here, we provide an overview of the conventional and alternative mechanisms through which thermogenic adipocytes selectively remove damaged parts of mitochondria and how macrophages participate in the MQC system by removing extracellular mitochondrial waste to maintain the thermogenic function of BAT.
    Keywords:  adipocytes; extracellular vesicles; immune cells; metabolism; mitochondrial transfer; thermogenesis
  12. Cell Mol Life Sci. 2022 Oct 29. 79(11): 574
      Through their role in energy generation and regulation of several vital pathways, including apoptosis and inflammation, mitochondria are critical for the life of eukaryotic organisms. Mitochondrial dysfunction is a major problem implicated in the etiology of many pathologies, including neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), diabetes, cardiovascular diseases, and many others. Proteotoxic stress, here defined as a reduction in bioenergetic activity induced by the accumulation of aberrant proteins in the mitochondria, is likely to be implicated in disease-linked mitochondrial and cellular decline. Various quality control pathways, such as mitochondrial unfolded protein response (mtUPR), the ubiquitin (Ub)-dependent degradation of aberrant mitochondrial proteins, and mitochondria-specific autophagy (mitophagy), respond to proteotoxic stress and eliminate defective proteins or dysfunctional mitochondria. This work provides a concise review of mechanisms by which disease-linked aberrant proteins affect mitochondrial function and an overview of mitochondrial quality control pathways that counteract mitochondrial proteotoxicity. We focus on mitochondrial quality control mechanisms relying on the Ub-mediated protein degradation, such as mitochondria-specific autophagy and the mitochondrial arm of the Ub proteasome system (UPS). We highlight the importance of a widening perspective of how these pathways protect mitochondria from proteotoxic stress to better understand mitochondrial proteotoxicity in overlapping pathophysiological pathways. Implications of these mechanisms in disease development are also briefly summarized.
    Keywords:  Mitochondria; Mitophagy; Proteotoxicity; Quality control; Ubiquitin
  13. JCI Insight. 2022 Oct 24. pii: e156222. [Epub ahead of print]7(20):
      Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis elegans animal models of DLD deficiency generated by graded feeding of dld-1(RNAi) revealed that full or partial reduction of DLD-1 expression recapitulated increased pyruvate levels typical of pyruvate dehydrogenase complex deficiency and significantly altered animal survival and health, with reductions in brood size, adult length, and neuromuscular function. DLD-1 deficiency dramatically increased mitochondrial unfolded protein stress response induction and adaptive mitochondrial proliferation. While ATP levels were reduced, respiratory chain enzyme activities and in vivo mitochondrial membrane potential were not significantly altered. DLD-1 depletion directly correlated with the induction of mitochondrial stress and impairment of worm growth and neuromuscular function. The safety and efficacy of dichloroacetate, thiamine, riboflavin, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), l-carnitine, and lipoic acid supplemental therapies empirically used for human DLD disease were objectively evaluated by life span and mitochondrial stress response studies. Only dichloroacetate and thiamine showed individual and synergistic therapeutic benefits. Collectively, these C. elegans dld-1(RNAi) animal model studies demonstrate the translational relevance of preclinical modeling of disease mechanisms and therapeutic candidates. Results suggest that clinical trials are warranted to evaluate the safety and efficacy of dichloroacetate and thiamine in human DLD disease.
    Keywords:  Drug therapy; Genetics; Metabolism; Mitochondria
  14. Orphanet J Rare Dis. 2022 Oct 24. 17(1): 386
      BACKGROUND: Variants in the mitochondrial complex I assembly factor, NUBPL are associated with a rare cause of complex I deficiency mitochondrial disease. Patients affected by complex I deficiency harboring homozygous NUBPL variants typically have neurological problems including seizures, intellectual disability, and ataxia associated with cerebellar hypoplasia. Thus far only 19 cases have been reported worldwide, and no treatment is available for this rare disease.METHODS: To investigate the pathogenesis of NUBPL-associated complex I deficiency, and for translational studies, we generated a knock-in mouse harboring a patient-specific variant Nubpl c.311T>C; p. L104P reported in three families.
    RESULTS: Similar to Nubpl global knockout mice, the Nubpl p. L104P homozygous mice are lethal at embryonic day E10.5, suggesting that the Nubpl p. L104P variant is likely a hypomorph allele. Given the recent link between Parkinson's disease and loss-of-function NUBPL variants, we also explored aging-related behaviors and immunocytochemical changes in Nubpl hemizygous mice and did not find significant behavioral and pathological changes for alpha-synuclein and oxidative stress markers .
    CONCLUSION: Our data suggest that homozygotes with Nubpl variants, similar to the null mice, are lethal, and heterozygotes are phenotypically and neuropathologically normal. We propose that a tissue-specific knockout strategy is required to establish a mouse model of Nubpl-associated complex I deficiency disorder for future mechanistic and translational studies.
    Keywords:  Complex I deficiency; Mitochondria; Mouse model; NUBPL; Parkinson’s disease
  15. PLoS One. 2022 ;17(10): e0276883
      BACKGROUND: Mitochondrial diseases are a large group of genetically heterogeneous and clinically diverse disorders. Diagnosis often takes many years for which treatment may not exist. Registries are often used to conduct research, establish natural disease progression, engage the patient community, and develop best disease management practices. In Canada, there are limited centralized registries for mitochondrial disease patients, presenting a challenge for patients and professionals.OBJECTIVE: To support the creation of such a registry, a systematic scoping review was conducted to map the landscape of mitochondrial disease patient registries worldwide, with a focus on registry design and challenges. Furthermore, it addresses a knowledge gap by providing a narrative synthesis of published literature that describes these registries.
    METHODS: Arksey and O'Malley's methodological framework was followed to systematically search English-language literature in PubMed and CINAHL describing the designs of mitochondrial disease patient registries, supplemented by a grey literature search. Data were extracted in Microsoft Excel. Stakeholder consultations were also performed with patient caregivers, advocates, and researchers to provide perspectives beyond those found in the literature. These data were thematically analyzed and were reported in accordance with the PRISMA-ScR reporting guidelines.
    RESULTS: A total of 17 articles were identified describing 13 unique registries located in North America, Europe, Australia, and West Asia. These papers described the registries' designs, their strengths, and weaknesses, as well as their tangible outcomes such as facilitating recruitment for research and supporting epidemiological studies.
    CONCLUSION: Based on our findings in this review, recommendations were formulated. These include establishing registry objectives, respecting patients and their roles in the registry, adopting international data standards, data evaluations, and considerations to privacy legislation, among others. These recommendations could be used to support designing a future Canadian mitochondrial disease patient registry, and to further research directly engaging these registries worldwide.
  16. Front Immunol. 2022 ;13 1017401
      Kawasaki disease is a systemic vasculitis, especially of the coronary arteries, affecting children. Despite extensive research, much is still unknown about the principal driver behind the amplified inflammatory response. We propose mitochondria may play a critical role. Mitochondria serve as a central hub, influencing energy generation, cell proliferation, and bioenergetics. Regulation of these biological processes, however, comes at a price. Release of mitochondrial DNA into the cytoplasm acts as damage-associated molecular patterns, initiating the development of inflammation. As a source of reactive oxygen species, they facilitate activation of the NLRP3 inflammasome. Kawasaki disease involves many of these inflammatory pathways. Progressive mitochondrial dysfunction alters the activity of immune cells and may play a role in the pathogenesis of Kawasaki disease. Because they contain their own genome, mitochondria are susceptible to mutation which can propagate their dysfunction and immunostimulatory potential. Population-specific variants in mitochondrial DNA have also been linked to racial disparities in disease risk and treatment response. Our objective is to critically examine the current literature of mitochondria's role in coordinating proinflammatory signaling pathways, focusing on potential mitochondrial dysfunction in Kawasaki disease. No association between impaired mitochondrial function and Kawasaki disease exists, but we suggest a relationship between the two. We hypothesize a framework of mitochondrial determinants that may contribute to ethnic/racial disparities in the progression of Kawasaki disease.
    Keywords:  Kawasaki disease; inflammasome; inflammation; mitochondria; mitochondrial DNA; mitophagy; reactive oxygen species
  17. Innovation (Camb). 2022 Nov 08. 3(6): 100329
      Pathogenic mitochondrial DNA (mtDNA) mutations can cause a variety of human diseases. The recent development of genome-editing technologies to manipulate mtDNA, such as mitochondria-targeted DNA nucleases and base editors, offer a promising way for curing mitochondrial diseases caused by mtDNA mutations. The CRISPR-Cas9 system is a widely used tool for genome editing; however, its application in mtDNA editing is still under debate. In this study, we developed a mito-Cas9 system by adding the mitochondria-targeted sequences and 3' untranslated region of nuclear-encoded mitochondrial genes upstream and downstream of the Cas9 gene, respectively. We confirmed that the mito-Cas9 system was transported into mitochondria and enabled knockin of exogenous single-stranded DNA oligonucleotides (ssODNs) into mtDNA based on proteinase and DNase protection assays. Successful knockin of exogenous ssODNs into mtDNA was further validated using polymerase chain reaction-free third-generation sequencing technology. We also demonstrated that RS-1, an agonist of RAD51, significantly increased knockin efficiency of the mito-Cas9 system. Collectively, we provide direct evidence that mtDNA can be edited using the CRISPR-Cas9 system. The mito-Cas9 system could be optimized as a promising approach for the treatment of mitochondrial diseases caused by pathogenic mtDNA mutations, especially those with homoplasmic mtDNA mutations.
    Keywords:  mitochondrial disease; mtDNA editing, mito-Cas9; third-generation sequencing
  18. J Clin Invest. 2022 Oct 27. pii: e154684. [Epub ahead of print]
      Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identify a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that results in atrophy of the spleen and thymus and causes a peripheral white blood cell deficiency. We demonstrate that the leukopenia is caused by α-fetoprotein, which requires copper and the cell surface receptor CCR5 to promote white blood cell death. We further show that α-fetoprotein expression is upregulated in several cell types upon inhibition of oxidative phosphorylation, including a muscle cell model of Barth syndrome. Collectively, our data argue that α-fetoprotein secreted by bioenergetically stressed tissue suppresses the immune system, an effect which may explain the recurrent infections that are observed in a subset of mitochondrial diseases or in other disorders with mitochondrial involvement.
    Keywords:  Metabolism; Mitochondria
  19. Nat Commun. 2022 Oct 27. 13(1): 6406
      Translation termination requires release factors that read a STOP codon in the decoding center and subsequently facilitate the hydrolysis of the nascent peptide chain from the peptidyl tRNA within the ribosome. In human mitochondria eleven open reading frames terminate in the standard UAA or UAG STOP codon, which can be recognized by mtRF1a, the proposed major mitochondrial release factor. However, two transcripts encoding for COX1 and ND6 terminate in the non-conventional AGA or AGG codon, respectively. How translation termination is achieved in these two cases is not known. We address this long-standing open question by showing that the non-canonical release factor mtRF1 is a specialized release factor that triggers COX1 translation termination, while mtRF1a terminates the majority of other mitochondrial translation events including the non-canonical ND6. Loss of mtRF1 leads to isolated COX deficiency and activates the mitochondrial ribosome-associated quality control accompanied by the degradation of COX1 mRNA to prevent an overload of the ribosome rescue system. Taken together, these results establish the role of mtRF1 in mitochondrial translation, which had been a mystery for decades, and lead to a comprehensive picture of translation termination in human mitochondria.
  20. Proc Natl Acad Sci U S A. 2022 Nov;119(44): e2121273119
      Axon regeneration is an energy-demanding process that requires active mitochondrial transport. In contrast to the central nervous system (CNS), axonal mitochondrial transport in regenerating axons of the peripheral nervous system (PNS) increases within hours and sustains for weeks after injury. Yet, little is known about targeting mitochondria in nervous system repair. Here, we report the induction of sustained axon regeneration, neural activities in the superior colliculus (SC), and visual function recovery after optic nerve crush (ONC) by M1, a small molecule that promotes mitochondrial fusion and transport. We demonstrated that M1 enhanced mitochondrial dynamics in cultured neurons and accelerated in vivo axon regeneration in the PNS. Ex vivo time-lapse imaging and kymograph analysis showed that M1 greatly increased mitochondrial length, axonal mitochondrial motility, and transport velocity in peripheral axons of the sciatic nerves. Following ONC, M1 increased the number of axons regenerating through the optic chiasm into multiple subcortical areas and promoted the recovery of local field potentials in the SC after optogenetic stimulation of retinal ganglion cells, resulting in complete recovery of the pupillary light reflex, and restoration of the response to looming visual stimuli was detected. M1 increased the gene expression of mitochondrial fusion proteins and major axonal transport machinery in both the PNS and CNS neurons without inducing inflammatory responses. The knockdown of two key mitochondrial genes, Opa1 or Mfn2, abolished the growth-promoting effects of M1 after ONC, suggesting that maintaining a highly dynamic mitochondrial population in axons is required for successful CNS axon regeneration.
    Keywords:  axon regeneration; mitochondrial dynamics; optic nerve crush; peripheral nerve injury; visual function recovery
  21. Mitochondrion. 2022 Oct 20. pii: S1567-7249(22)00086-1. [Epub ahead of print]
      The plastic architecture of the mitochondrial network and its dynamic structure play crucial roles ensuring that varying energetic demands are rapidly met. Given the brain's high energy demand, mitochondria play a particularly critical role in neuronal and axonal energy homeostasis With ageing physiological properties of the organism deteriorate, and are associated with loss of cellular homeostasis, accumulation of dysfunctional organelles and damaged macromolecules. Thus, mitochondrial loss of efficiency is likely to be both a cause and a consequence of ageing. Additionally distinct cellular events can contribute to oxidative stress, disruption of metabolism and mitochondria homeostasis, resulting in neuropathology. However, although the correlation between ageing and mitochondria disfunction is well established, the response to oxidative stress, particularly proteostasis, remains to be fully elucidated. The work here described explores the degradation of mitochondria oxidative stress-response mechanisms with ageing in human cells, addressing the physiological effects on proteostasis, focused on its role in differentiating between healthy and pathological ageing. Increased protein aggregation appears to be tightly related to impairment of ageing mitochondria response to oxidative stress, and antioxidative agents are shown to have a progressive protective effect with age; cells from old individuals show higher susceptibility to oxidative stress, in terms of protein aggregation, cell viability, or mitochondria homeostasis. These results support the antioxidant properties of flavonoids as a good therapeutic strategy for age-related diseases. Given their protective effect, this family of compounds can be of strategic therapeutic value for protein-aggregation related diseases.
  22. Int J Mol Sci. 2022 Oct 11. pii: 12105. [Epub ahead of print]23(20):
      The quality control of mitochondria is critical for the survival of cells, and defects in the pathways required for this quality control can lead to severe disease. A key quality control mechanism in cells is mitophagy, which functions to remove damaged mitochondria under conditions of various stresses. Defective mitophagy can lead to a number of diseases including neurodegeneration. It has been proposed that an enhancement of mitophagy can improve cell survival, enhance neuronal function in neurodegeneration and extend health and lifespans. In this review, we highlight the role of deubiquitinating enzymes (DUBs) in the regulation of mitophagy. We summarise the current knowledge on DUBs that regulate mitophagy as drug targets and provide a list of small molecule inhibitors that are valuable tools for the further development of therapeutic strategies targeting the mitophagy pathway in neurodegeneration.
    Keywords:  DUB inhibitors; Parkin; Parkinson disease; deubiquitinating enzymes; mitophagy
  23. J Neurosci. 2022 Oct 24. pii: JN-RM-0545-22. [Epub ahead of print]
      Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. In this study, we generated a transgenic model by crossing germline Parkin-/- mice with PolgAD257A mice, an established model of premature aging and mitochondrial stress. We hypothesized that loss of Parkin-/- in PolgAD257A/D257A mice would exacerbate mitochondrial dysfunction, leading to loss of dopamine neurons and nigral-striatal specific neurobehavioral motor dysfunction. We found that aged Parkin-/-/PolgAD257A/D257A male and female mice exhibited severe behavioral deficits, nonspecific to the nigral-striatal pathway, with neither dopaminergic neurodegeneration nor reductions in striatal dopamine. We saw no difference in expression levels of nuclear-encoded subunits of mitochondrial markers and mitochondrial complex I and IV activities, though we did observe substantial reductions in mitochondrial-encoded COX41I, indicating mitochondrial dysfunction as a result of PolgAD257A/D257A mtDNA mutations. Expression levels of mitophagy markers LC3I/LC3II remained unchanged between cohorts, suggesting no overt mitophagy defects. Expression levels of the parkin substrates, VDAC, NLRP3, and AIMP2 remained unchanged, suggesting no parkin dysfunction. In summary, we were unable to observe dopaminergic neurodegeneration with corresponding nigral-striatal neurobehavioral deficits, nor Parkin or mitochondrial dysfunction in Parkin-/-/PolgAD257A/D257A mice. These findings support a lack of synergism of Parkin loss on mitochondrial dysfunction in mouse models of mitochondrial deficits.SIGNIFICANCE STATEMENT:Producing a mouse model of PD that is etiologically relevant, recapitulates clinical hallmarks, and exhibits reproducible results is crucial to understanding the underlying pathology and in developing disease-modifying therapies. Here, we show that Parkin-/-/PolgAD257A/D257A mice, a previously reported PD mouse model, fails to reproduce a Parkinsonian phenotype. We show that these mice do not display dopaminergic neurodegeneration nor nigral-striatal-dependent motor deficits. Furthermore, we report that Parkin loss does not synergize with mitochondrial dysfunction. Our results demonstrate that Parkin-/-/PolgAD257A/D257A mice are not a reliable model for PD and adds to a growing body of work demonstrating that Parkin loss does not synergize with mitochondrial dysfunction in mouse models of mitochondrial deficits.
  24. Int J Mol Sci. 2022 Oct 20. pii: 12603. [Epub ahead of print]23(20):
      Mitochondrial dysfunction has been implicated in the pathogenesis of a number of neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, and progressive supranuclear palsy. This article is concerned specifically with mitochondrial dysfunction as defined by reduced capacity for ATP production, the role of depleted levels of key nutritionally related metabolites, and the potential benefit of supplementation with specific nutrients of relevance to normal mitochondrial function in the above neurodegenerative disorders. The article provides a rationale for a combination of CoQ10, B-vitamins/NADH, L-carnitine, vitamin D, and alpha-lipoic acid for the treatment of the above neurodegenerative disorders.
    Keywords:  B-vitamins; alpha-lipoic acid; coenzyme Q10; l-carnitine; mitochondrial dysfunction; neurodegenerative disorders; selenium; vitamin D
  25. Int J Mol Sci. 2022 Oct 21. pii: 12676. [Epub ahead of print]23(20):
      Mitophagy is the selective degradation of mitochondria by autophagy. It promotes the turnover of mitochondria and prevents the accumulation of dysfunctional mitochondria, which can lead to cellular degeneration. Mitophagy is known to be altered in several pathological conditions, especially in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We recently demonstrated an increase in autophagy flux in lymphoblasts from ALS patients bearing a mutation in SOD1. Thus, the identification of mitophagy inhibitors may be a therapeutic option to recover mitochondrial homeostasis. Here, using a phenotypic mitophagy assay, we identified a new mitophagy inhibitor, the small molecule named IGS2.7 from the MBC library. Interestingly, the treatment of different cellular and in vivo models of ALS with mutations on SOD1 and TARDBP with this inhibitor restores autophagy to control levels. These results point mitophagy inhibitors, especially IGS2.7, to a new therapeutic approach for familial ALS patients.
    Keywords:  amyotrophic lateral sclerosis; drug discovery; mitophagy; phenotypic assay
  26. J Transl Med. 2022 Oct 22. 20(1): 483
      Metabolic diseases, including obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD), are rising in both incidence and prevalence and remain a major global health and socioeconomic burden in the twenty-first century. Despite an increasing understanding of these diseases, the lack of effective treatments remains an ongoing challenge. Mitochondria are key players in intracellular energy production, calcium homeostasis, signaling, and apoptosis. Emerging evidence shows that mitochondrial dysfunction participates in the pathogeneses of metabolic diseases. Exogenous supplementation with healthy mitochondria is emerging as a promising therapeutic approach to treating these diseases. This article reviews recent advances in the use of mitochondrial transplantation therapy (MRT) in such treatment.
    Keywords:  Diabetes; Extracellular vesicles; Mitochondrial transfer; Nonalcoholic fatty liver disease; Obesity
  27. Autophagy. 2022 Oct 25.
      Mitophagy is a key intracellular process that selectively removes damaged mitochondria to prevent their accumulation that can cause neuronal degeneration. During mitophagy, PINK1 (PTEN induced kinase 1), a serine/threonine kinase, works with PRKN/parkin, an E3 ubiquitin ligase, to target damaged mitochondria to the lysosome for degradation. Mutations in the PINK1 and PRKN genes cause early-onset Parkinson disease that is also associated with mitochondrial dysfunction. There are a large number of reports indicating the critical role of PINK1 in mitophagy. However, most of these findings were obtained from in vitro experiments with exogenous PINK1 expression and acute damage of mitochondria by toxins. Recent studies using novel animal models suggest that PINK1-PRKN can also function independent of mitochondria. In this review, we highlight the major differences between in vitro and in vivo models for investigating PINK1 and discuss the potential mechanisms underlying these differences with the aim of understanding how PINK1 functions under different circumstances.
    Keywords:  Mitochondria dysfunction; PINK1; PRKN; Parkinson disease; mitophagy
  28. Cell Mol Life Sci. 2022 Oct 29. 79(11): 573
      Mitochondrial dynamics are balanced fission and fusion events that regulate mitochondrial morphology, and alteration in these events results in mitochondrial dysfunction and contributes to many diseases, including tumorigenesis. Ovarian cancer (OC) cells exhibit fragmented mitochondria, but the mechanism by which mitochondrial dynamics regulators contribute to OC is considerably less clear. Here, we elucidated the potential role of Mfn2-mediated mitochondrial fusion in OC and present evidence that genetic or pharmacological activation of Mfn2 leads to mitochondrial fusion and reduces ROS generation, which correlates with reduced cell proliferation, invasion, migration, and EMT in OC cells. Also, increased mitochondrial fusion promotes the F-actin remodeling, reduces lamellipodia formation, and thus reduces EMT. Increased expression of Mfn2 triggers AMPK, promotes autophagy, reduces ROS, and suppresses OC progression by downregulating  the p-mTOR (2481 and 2448) and p-ERK axis. OC patients with higher Mfn2 expression have better survival than those with lower Mfn2 levels. Our findings demonstrate that restoration of Mfn2-mediated mitochondrial fusion suppressed OC progression and suggest that this process could be a potential strategy in OC treatment.
    Keywords:  AMPK; Autophagy; EMT; Mfn2; Ovarian cancer; ROS
  29. Biomolecules. 2022 Oct 01. pii: 1405. [Epub ahead of print]12(10):
      Oxidative stress and mitochondrial dysfunction are associated with the pathogenesis of several human diseases. The excessive generation of reactive oxygen species (ROS) and/or lack of adequate antioxidant defenses causes DNA mutations in mitochondria, damages the mitochondrial respiratory chain, and alters membrane permeability and mitochondrial defense mechanisms. All these alterations are linked to the development of numerous diseases. Curcumin, an active ingredient of turmeric plant rhizomes, exhibits numerous biological activities (i.e., antioxidant, anti-inflammatory, anticancer, and antimicrobial). In recent years, many researchers have shown evidence that curcumin has the ability to reduce the oxidative stress- and mitochondrial dysfunction-associated diseases. In this review, we discuss curcumin's antioxidant mechanism and significance in oxidative stress reduction and suppression of mitochondrial dysfunction in mammals. We also discuss the research gaps and give our opinion on how curcumin research in mammals should proceed moving forward.
    Keywords:  anti-inflammatory; anticancer; antimicrobial; antioxidant; curcumin; mammals; mitochondrial dysfunction; oxidative stress
  30. Mol Cell. 2022 Oct 21. pii: S1097-2765(22)00960-1. [Epub ahead of print]
      Coenzyme Q (CoQ) is a redox-active lipid essential for core metabolic pathways and antioxidant defense. CoQ is synthesized upon the mitochondrial inner membrane by an ill-defined "complex Q" metabolon. Here, we present structure-function analyses of a lipid-, substrate-, and NADH-bound complex comprising two complex Q subunits: the hydroxylase COQ7 and the lipid-binding protein COQ9. We reveal that COQ7 adopts a ferritin-like fold with a hydrophobic channel whose substrate-binding capacity is enhanced by COQ9. Using molecular dynamics, we further show that two COQ7:COQ9 heterodimers form a curved tetramer that deforms the membrane, potentially opening a pathway for the CoQ intermediates to translocate from the bilayer to the proteins' lipid-binding sites. Two such tetramers assemble into a soluble octamer with a pseudo-bilayer of lipids captured within. Together, these observations indicate that COQ7 and COQ9 cooperate to access hydrophobic precursors within the membrane and coordinate subsequent synthesis steps toward producing CoQ.
    Keywords:  COQ7; COQ9; coenzyme Q; di-iron proteins; mitochondria; protein-lipid complex; protein-membrane interaction; quinone biosynthesis
  31. Mov Disord. 2022 Oct 29.
      BACKGROUND: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear.OBJECTIVE: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort.
    METHODS: We performed a cross-sectional analysis of cervical spinal cord (C1-C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age.
    RESULTS: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < -0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time.
    CONCLUSIONS: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  ENIGMA-ataxia; Friedreich's ataxia; MRI; SCT; spinal cord