bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2020‒10‒25
twenty-five papers selected by
Edmond Chan
Queen’s University, School of Medicine

  1. J Cell Biol. 2020 Dec 07. pii: e202002144. [Epub ahead of print]219(12):
    English AM, Schuler MH, Xiao T, Kornmann B, Shaw JM, Hughes AL.
      Mitochondria are dynamic organelles with essential roles in signaling and metabolism. We recently identified a cellular structure called the mitochondrial-derived compartment (MDC) that is generated from mitochondria in response to amino acid overabundance stress. How cells form MDCs is unclear. Here, we show that MDCs are dynamic structures that form and stably persist at sites of contact between the ER and mitochondria. MDC biogenesis requires the ER-mitochondria encounter structure (ERMES) and the conserved GTPase Gem1, factors previously implicated in lipid exchange and membrane tethering at ER-mitochondria contacts. Interestingly, common genetic suppressors of abnormalities displayed by ERMES mutants exhibit distinct abilities to rescue MDC formation in ERMES-depleted strains and are incapable of rescuing MDC formation in cells lacking Gem1. Thus, the function of ERMES and Gem1 in MDC biogenesis may extend beyond their conventional role in maintaining mitochondrial phospholipid homeostasis. Overall, this study identifies an important function for ER-mitochondria contacts in the biogenesis of MDCs.
  2. Cell Stem Cell. 2020 Oct 10. pii: S1934-5909(20)30493-8. [Epub ahead of print]
    Mansell E, Sigurdsson V, Deltcheva E, Brown J, James C, Miharada K, Soneji S, Larsson J, Enver T.
      Aging is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing increased risk of immune compromise, anemia, and malignancy. We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs with transcriptional features and functional attributes characteristic of young HSCs, including a high rate of transcription and balanced lineage-affiliated programs. Strikingly, MMP is a stronger determinant of the quantitative and qualitative transcriptional state of HSCs than chronological age, and transcriptional consequences of manipulation of MMP in HSCs within their native niche suggest a causal relationship. Accordingly, we show that pharmacological enhancement of MMP in old HSCs in vivo increases engraftment potential upon transplantation and reverses myeloid-biased peripheral blood output at steady state. Our results demonstrate that MMP is a source of heterogeneity in old HSCs, and its pharmacological manipulation can alter transcriptional programs with beneficial consequences for function.
    Keywords:  Aging; Hematopoietc Stem Cell; Lineage bias; Mitochondria; Mitochondrial Membrane Potential; Mitoquinol; Transcription Rate
  3. Cell Discov. 2020 ;6 67
    Wang W, Chen X, Zhang L, Yi J, Ma Q, Yin J, Zhuo W, Gu J, Yang M.
      The translocase of the outer mitochondrial membrane (TOM) complex is the main entry gate for mitochondrial precursor proteins synthesized on cytosolic ribosomes. Here we report the single-particle cryo-electron microscopy (cryo-EM) structure of the dimeric human TOM core complex (TOM-CC). Two Tom40 β-barrel proteins, connected by two Tom22 receptor subunits and one phospholipid, form the protein-conducting channels. The small Tom proteins Tom5, Tom6, and Tom7 surround the channel and have notable configurations. The distinct electrostatic features of the complex, including the pronounced negative interior and the positive regions at the periphery and center of the dimer on the intermembrane space (IMS) side, provide insight into the preprotein translocation mechanism. Further, two dimeric TOM complexes may associate to form tetramer in the shape of a parallelogram, offering a potential explanation into the unusual structural features of Tom subunits and a new perspective of viewing the import of mitochondrial proteins.
    Keywords:  Cryoelectron microscopy; Structural biology
  4. PLoS Genet. 2020 Oct 21. 16(10): e1008844
    Terriente-Felix A, Wilson EL, Whitworth AJ.
      Balanced mitochondrial fission and fusion play an important role in shaping and distributing mitochondria, as well as contributing to mitochondrial homeostasis and adaptation to stress. In particular, mitochondrial fission is required to facilitate degradation of damaged or dysfunctional units via mitophagy. Two Parkinson's disease factors, PINK1 and Parkin, are considered key mediators of damage-induced mitophagy, and promoting mitochondrial fission is sufficient to suppress the pathological phenotypes in Drosophila Pink1/parkin mutants. We sought additional factors that impinge on mitochondrial dynamics and which may also suppress Pink1/parkin phenotypes. We found that the Drosophila phosphatidylinositol 4-kinase IIIβ homologue, Four wheel drive (Fwd), promotes mitochondrial fission downstream of the pro-fission factor Drp1. Previously described only as male sterile, we identified several new phenotypes in fwd mutants, including locomotor deficits and shortened lifespan, which are accompanied by mitochondrial dysfunction. Finally, we found that fwd overexpression can suppress locomotor deficits and mitochondrial disruption in Pink1/parkin mutants, consistent with its function in promoting mitochondrial fission. Together these results shed light on the complex mechanisms of mitochondrial fission and further underscore the potential of modulating mitochondrial fission/fusion dynamics in the context of neurodegeneration.
  5. Sci Adv. 2020 Oct;pii: eabe5310. [Epub ahead of print]6(43):
    Kory N, Uit de Bos J, van der Rijt S, Jankovic N, Güra M, Arp N, Pena IA, Prakash G, Chan SH, Kunchok T, Lewis CA, Sabatini DM.
      The nicotinamide adenine dinucleotide (NAD+/NADH) pair is a cofactor in redox reactions and is particularly critical in mitochondria as it connects substrate oxidation by the tricarboxylic acid (TCA) cycle to adenosine triphosphate generation by the electron transport chain (ETC) and oxidative phosphorylation. While a mitochondrial NAD+ transporter has been identified in yeast, how NAD enters mitochondria in metazoans is unknown. Here, we mine gene essentiality data from human cell lines to identify MCART1 (SLC25A51) as coessential with ETC components. MCART1-null cells have large decreases in TCA cycle flux, mitochondrial respiration, ETC complex I activity, and mitochondrial levels of NAD+ and NADH. Isolated mitochondria from cells lacking or overexpressing MCART1 have greatly decreased or increased NAD uptake in vitro, respectively. Moreover, MCART1 and NDT1, a yeast mitochondrial NAD+ transporter, can functionally complement for each other. Thus, we propose that MCART1 is the long sought mitochondrial transporter for NAD in human cells.
  6. Mol Oncol. 2020 Oct 17.
    Shi L, Liu J, Peng Y, Zhang J, Dai X, Zhang S, Wang Y, Liu J, Long J.
      Dynamin-related protein 1 (Drp1) is a cytosolic protein responsible for mitochondrial fission and is essential in the initiation and development of several human diseases, including cancer. However, the regulation of Drp1, especially of its ubiquitination, remains unclear. In this study, we report that the ovarian tumor-associated protease deubiquitinase 6A (OTUD6A) deubiquitylates and stabilizes Drp1, thereby facilitating regulation of mitochondrial morphology and tumorigenesis. OTUD6A is upregulated in human patients with colorectal cancer. Depletion of OTUD6A leads to lower Drp1 levels and suppressed mitochondrial fission and the affected cells are consequently less prone to tumorigenesis. Conversely, overexpression of OTUD6A increases Drp1 levels and its protein half-life and enhances cancer cell growth. Therefore, our results reveal a novel upstream protein of Drp1, and its role in tumorigenesis that is played, in part, through the activation of mitochondrial fission mediated by Drp1.
    Keywords:  Drp1; OTUD6A; cancer cell growth; deubiquitination; mitochondrial fission
  7. J Cell Sci. 2020 Oct 18. pii: jcs.247379. [Epub ahead of print]
    Townley AR, Wheatley SP.
      Survivin is a cancer-associated protein that is pivotal for cellular life and death: it is an essential mitotic protein and an inhibitor of apoptosis. In cancer cells, a small pool of survivin localises to the mitochondria, the function of which remains to be elucidated. Here, we report that mitochondrial survivin inhibits the selective form of autophagy, called "mitophagy", causing an accumulation of respiratory defective mitochondria. Mechanistically the data reveal that survivin prevents recruitment of the E3-ubiquitin ligase Parkin to mitochondria and their subsequent recognition by the autophagosome. The data also demonstrate that cells in which mitophagy has been blocked by survivin expression have an increased dependency on glycolysis. As these effects were found exclusively in cancer cells they suggest that the primary act of mitochondrial survivin is to steer cells towards the implementation of the Warburg transition by inhibiting mitochondrial turnover, which enables them to adapt and survive.
    Keywords:  Cancer; Mitochondria; Mitophagy; Respiration; Survivin
  8. Cell Mol Life Sci. 2020 Oct 19.
    Romanello V, Sandri M.
      The dynamic coordination of processes controlling the quality of the mitochondrial network is crucial to maintain the function of mitochondria in skeletal muscle. Changes of mitochondrial proteolytic system, dynamics (fusion/fission), and mitophagy induce pathways that affect muscle mass and performance. When muscle mass is lost, the risk of disease onset and premature death is dramatically increased. For instance, poor quality of muscles correlates with the onset progression of several age-related disorders such as diabetes, obesity, cancer, and aging sarcopenia. To date, there are no drug therapies to reverse muscle loss, and exercise remains the best approach to improve mitochondrial health and to slow atrophy in several diseases. This review will describe the principal mechanisms that control mitochondrial quality and the pathways that link mitochondrial dysfunction to muscle mass regulation.
    Keywords:  Atrophy; Autophagy; FGF21; Fission; Fusion; Mitochondria; Mitochondrial proteostasis; Mitophagy; Myokines; Skeletal muscle
  9. Commun Biol. 2020 Oct 21. 3(1): 596
    Lobo MJ, Reverte-Salisa L, Chao YC, Koschinski A, Gesellchen F, Subramaniam G, Jiang H, Pace S, Larcom N, Paolocci E, Pfeifer A, Zanivan S, Zaccolo M.
      Programmed degradation of mitochondria by mitophagy, an essential process to maintain mitochondrial homeostasis, is not completely understood. Here we uncover a regulatory process that controls mitophagy and involves the cAMP-degrading enzyme phosphodiesterase 2A2 (PDE2A2). We find that PDE2A2 is part of a mitochondrial signalosome at the mitochondrial inner membrane where it interacts with the mitochondrial contact site and organizing system (MICOS). As part of this compartmentalised signalling system PDE2A2 regulates PKA-mediated phosphorylation of the MICOS component MIC60, resulting in modulation of Parkin recruitment to the mitochondria and mitophagy. Inhibition of PDE2A2 is sufficient to regulate mitophagy in the absence of other triggers, highlighting the physiological relevance of PDE2A2 in this process. Pharmacological inhibition of PDE2 promotes a 'fat-burning' phenotype to retain thermogenic beige adipocytes, indicating that PDE2A2 may serve as a novel target with potential for developing therapies for metabolic disorders.
  10. Cell Death Differ. 2020 Oct 21.
    Zhang Y, Xu X, Hu M, Wang X, Cheng H, Zhou R.
      Selective autophagic degradation of mitochondria (mitophagy) is important in maintaining proper cellular homeostasis. Here, we found that SPATA33 is a novel autophagy mediator for mitophagy in testis. The SPATA33 protein localizes on mitochondria via its binding of the carboxyl terminal with the outer mitochondrial membrane protein VDAC2. Upon starvation induction, SPATA33 is recruited to autophagosome by binding the autophagy machinery ATG16L1 via its N-terminal along with mitochondria. Notably, Spata33 knockout inhibited autophagy and overexpression can promote autophagosome formation for mitochondrial sequestration. Therefore, SPATA33 confers selectivity for mitochondrial degradation and promotes mitophagy in male germline cells.
  11. Front Cell Dev Biol. 2020 ;8 572182
    Joaquim M, Escobar-Henriques M.
      Mitochondria entail an incredible dynamism in their morphology, impacting death signaling and selective elimination of the damaged organelles. In turn, by recycling the superfluous or malfunctioning mitochondria, mostly prevalent during aging, mitophagy contributes to maintain a healthy mitochondrial network. Mitofusins locate at the outer mitochondrial membrane and control the plastic behavior of mitochondria, by mediating fusion events. Besides deciding on mitochondrial interconnectivity, mitofusin 2 regulates physical contacts between mitochondria and the endoplasmic reticulum, but also serves as a decisive docking platform for mitophagy and apoptosis effectors. Thus, mitofusins integrate multiple bidirectional inputs from and into mitochondria and ensure proper energetic and metabolic cellular performance. Here, we review the role of mitofusins and mitophagy at the cross-road between life and apoptotic death decisions. Furthermore, we highlight the impact of this interplay on disease, focusing on how mitofusin 2 and mitophagy affect non-alcoholic fatty liver disease.
    Keywords:  MFN2; NAFLD; apoptosis; mitochondria; mitofusins; mitophagy
  12. Trends Cell Biol. 2020 Oct 19. pii: S0962-8924(20)30188-4. [Epub ahead of print]
    Gao S, Hu J.
      Mitochondria are highly dynamic organelles that constantly undergo fission and fusion. Disruption of mitochondrial dynamics undermines their function and causes several human diseases. The fusion of the outer (OMM) and inner mitochondrial membranes (IMM) is mediated by two classes of dynamin-like protein (DLP): mitofusin (MFN)/fuzzy onions 1 (Fzo1) and optic atrophy 1/mitochondria genome maintenance 1 (OPA1/Mgm1). Given the lack of structural information on these fusogens, the molecular mechanisms underlying mitochondrial fusion remain unclear, even after 20 years. Here, we review recent advances in structural studies of the mitochondrial fusion machinery, discuss their implication for DLPs, and summarize the pathogenic mechanisms of disease-causing mutations in mitochondrial fusion DLPs.
    Keywords:  Dynamin superfamily; Mitofusin/Fzo1; OPA1/Mgm1; cristae formation; mitochondrial fusion; structure
  13. Nat Rev Mol Cell Biol. 2020 Oct 22.
    Song J, Herrmann JM, Becker T.
      Mitochondria contain about 1,000-1,500 proteins that fulfil multiple functions. Mitochondrial proteins originate from two genomes: mitochondrial and nuclear. Hence, proper mitochondrial function requires synchronization of gene expression in the nucleus and in mitochondria and necessitates efficient import of mitochondrial proteins into the organelle from the cytosol. Furthermore, the mitochondrial proteome displays high plasticity to allow the adaptation of mitochondrial function to cellular requirements. Maintenance of this complex and adaptable mitochondrial proteome is challenging, but is of crucial importance to cell function. Defects in mitochondrial proteostasis lead to proteotoxic insults and eventually cell death. Different quality control systems monitor the mitochondrial proteome. The cytosolic ubiquitin-proteasome system controls protein transport across the mitochondrial outer membrane and removes damaged or mislocalized proteins. Concomitantly, a number of mitochondrial chaperones and proteases govern protein folding and degrade damaged proteins inside mitochondria. The quality control factors also regulate processing and turnover of native proteins to control protein import, mitochondrial metabolism, signalling cascades, mitochondrial dynamics and lipid biogenesis, further ensuring proper function of mitochondria. Thus, mitochondrial protein quality control mechanisms are of pivotal importance to integrate mitochondria into the cellular environment.
  14. FEBS Lett. 2020 Oct 21.
    Jeong S, Seong JH, Kang JH, Lee DS, Yim M.
      Dynamin-related protein 1 (DRP1) is a mitochondrial membrane GTPase and regulates mitochondrial fission. In this study, we found that the cytokine RANKL increased the expression of DRP1 and its receptor proteins, Fis1, Mid49, and Mid 51, during osteoclast formation in mouse bone marrow-derived macrophages. Inactivation of the kinase GSK3β appeared to induce DRP1 expression. DRP1 knockdown or the DRP1 inhibitor Mdivi1 suppressed osteoclast differentiation via downregulation of c-Fos and NFATc1, the key transcription factor for osteoclast formation. Finally, the DRP1 inhibitor suppressed lipopolysaccharide-induced osteoclast formation in a calvarial model and ovariectomy-induced bone loss in vivo. Taken together, our data demonstrate that DRP1 positively contributes to RANKL-induced osteoclast differentiation by regulating the c-Fos-NFATc1 axis, suggesting the importance of mitochondrial DRP1 in osteoclastogenesis.
    Keywords:  Bone loss; DRP1; NFATc1; Osteoclastogenesis; RANKL
  15. Nat Biotechnol. 2020 Oct 19.
    Cui L, Gouw AM, LaGory EL, Guo S, Attarwala N, Tang Y, Qi J, Chen YS, Gao Z, Casey KM, Bazhin AA, Chen M, Hu L, Xie J, Fang M, Zhang C, Zhu Q, Wang Z, Giaccia AJ, Gambhir SS, Zhu W, Felsher DW, Pegram MD, Goun EA, Le A, Rao J.
      Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach.
  16. Nat Cancer. 2020 Oct;1(10): 976-989
    Smith AL, Whitehall JC, Bradshaw C, Gay D, Robertson F, Blain AP, Hudson G, Pyle A, Houghton D, Hunt M, Sampson JN, Stamp C, Mallett G, Amarnath S, Leslie J, Oakley F, Wilson L, Baker A, Russell OM, Johnson R, Richardson CA, Gupta B, McCallum I, McDonald SA, Kelly S, Mathers JC, Heer R, Taylor RW, Perkins ND, Turnbull DM, Sansom OJ, Greaves LC.
      Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.
  17. Cells. 2020 Oct 21. pii: E2333. [Epub ahead of print]9(10):
    Petit PX, Ardilla-Osorio H, Penalvia L, Nathan E R.
      Tafazzin is a phospholipid transacylase that catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mutations of the tafazzin gene cause Barth syndrome, which is characterized by mitochondrial dysfunction and dilated cardiomyopathy, leading to premature death. However, the molecular mechanisms underlying the cause of mitochondrial dysfunction in Barth syndrome remain poorly understood. We again highlight the fact that the tafazzin deficiency is also linked to defective oxidative phosphorylation associated with oxidative stress. All the mitochondrial events are positioned in a context where mitophagy is a key element in mitochondrial quality control. Here, we investigated the role of tafazzin in mitochondrial homeostasis dysregulation and mitophagy alteration. Using a HeLa cell model of tafazzin deficiency, we show that dysregulation of tafazzin in HeLa cells induces alteration of mitophagy. Our findings provide some additional insights into mitochondrial dysfunction associated with Barth syndrome, but also show that mitophagy inhibition is concomitant with apoptosis dysfunction through the inability of abnormal mitochondrial cardiolipin to assume its role in cytoplasmic signal transduction. Our work raises hope that pharmacological manipulation of the mitophagic pathway together with mitochondrially targeted antioxidants may provide new insights leading to promising treatment for these highly lethal conditions.
    Keywords:  Barth syndrome; apoptosis; autophagy; cardiolipin; electron transport; mitochondria; tafazzin
  18. Elife. 2020 Oct 19. pii: e61119. [Epub ahead of print]9
    Franco A, Dang X, Walton EK, Ho JN, Zablocka B, Ly C, Miller TM, Baloh RH, Shy ME, Yoo AS, Dorn Ii GW.
      Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causal MFN2 mutation. In mice expressing human MFN2 T105M, intermittent mitofusin activation with a small molecule, MiM111, normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses. MiM111-treated MFN2 T105M mouse neurons exhibited accelerated primary outgrowth and greater post-axotomy regrowth, linked to enhanced mitochondrial motility. MiM111 is the first pre-clinical candidate for CMT2A.
    Keywords:  cell biology; mouse; neuroscience
  19. PLoS Genet. 2020 Oct 19. 16(10): e1009118
    Pareek G, Pallanck LJ.
      The m-AAA proteases play a critical role in the proteostasis of inner mitochondrial membrane proteins, and mutations in the genes encoding these proteases cause severe incurable neurological diseases. To further explore the biological role of the m-AAA proteases and the pathological consequences of their deficiency, we used a genetic approach in the fruit fly Drosophila melanogaster to inactivate the ATPase family gene 3-like 2 (AFG3L2) gene, which encodes a critical component of the m-AAA proteases. We found that null alleles of Drosophila AFG3L2 die early in development, but partial inactivation of AFG3L2 using RNAi allowed survival to the late pupal and adult stages of development. Flies with partial inactivation of AFG3L2 exhibited behavioral defects, neurodegeneration, accumulation of unfolded mitochondrial proteins, and diminished respiratory chain (RC) activity. Further work revealed that the reduced RC activity was primarily a consequence of severely diminished mitochondrial transcription and translation. These defects were accompanied by activation of the mitochondrial unfolded protein response (mito-UPR) and autophagy. Overexpression of mito-UPR components partially rescued the AFG3L2-deficient phenotypes, indicating that protein aggregation partly accounts for the defects of AFG3L2-deficient animals. Our work suggests that strategies designed to activate mitochondrial stress pathways and mitochondrial gene expression could be therapeutic in the diseases caused by mutations in AFG3L2.
  20. Cell Rep. 2020 Oct 20. pii: S2211-1247(20)31277-8. [Epub ahead of print]33(3): 108288
    Cibi DM, Bi-Lin KW, Shekeran SG, Sandireddy R, Tee N, Singh A, Wu Y, Srinivasan DK, Kovalik JP, Ghosh S, Seale P, Singh MK.
      Hypertrophic cardiomyopathy (HCM) is a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to physiological or pathological stress, prolonged hypertrophy can lead to heart failure. Here we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N-methyltransferase factors (Ehmts) act together to reduce expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of the pro-hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Our study demonstrates that Prdm16 protects the heart against age-dependent cardiac hypertrophy and heart failure.
    Keywords:  EHMT1/2; Myc; Prdm16; aging; cardiac fibrosis; cardiac hypertrophy; cardiac metabolism; heart failure; mitochondrial defects
  21. Sci Adv. 2020 Oct;pii: eaaz4452. [Epub ahead of print]6(43):
    Sural S, Liang CY, Wang FY, Ching TT, Hsu AL.
      Heat shock factor-1 (HSF-1) is a master regulator of stress responses across taxa. Overexpression of HSF-1 or genetic ablation of its conserved negative regulator, heat shock factor binding protein 1 (HSB-1), results in robust life-span extension in Caenorhabditis elegans Here, we found that increased HSF-1 activity elevates histone H4 levels in somatic tissues during development, while knockdown of H4 completely suppresses HSF-1-mediated longevity. Moreover, overexpression of H4 is sufficient to extend life span. Ablation of HSB-1 induces an H4-dependent increase in micrococcal nuclease protection of both nuclear chromatin and mitochondrial DNA (mtDNA), which consequently results in reduced transcription of mtDNA-encoded complex IV genes, decreased respiratory capacity, and a mitochondrial unfolded protein response-dependent life-span extension. Collectively, our findings reveal a previously unknown role of HSB-1/HSF-1 signaling in modulation of mitochondrial function via mediating histone H4-dependent regulation of mtDNA gene expression and concomitantly acting as a determinant of organismal longevity.
  22. Brain Commun. 2020 ;2(2): fcaa101
    Bevan RJ, Williams PA, Waters CT, Thirgood R, Mui A, Seto S, Good M, Morgan JE, Votruba M, Erchova I.
      A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerative events. To explore this, we quantified hippocampal dendritic and synaptic integrity and the learning and memory performance of aged Opa1 haploinsufficient mice carrying the Opa1Q285X mutation (B6; C3-Opa1Q285STOP ; Opa1+/- ). We demonstrate that heterozygous loss of Opa1 results in premature age-related loss of spines in hippocampal pyramidal CA1 neurons and a reduction in synaptic density in the hippocampus. This loss is associated with subtle memory deficits in both spatial novelty and object recognition. We hypothesize that metabolic failure to maintain normal neuronal activity at the level of a single spine leads to premature age-related memory deficits. These results highlight the importance of mitochondrial homeostasis for maintenance of neuronal function during ageing.
    Keywords:  OPA1; ageing; hippocampus; memory; optic atrophy
  23. J Cell Sci. 2020 Oct 23. pii: jcs.247353. [Epub ahead of print]
    Ansari MY, Ahmad N, Voleti S, Wase SJ, Novak K, Haqqi TM.
      Mitochondrial function is impaired in osteoarthritis (OA) but its impact on cartilage catabolism is not fully understood. Here, we investigated the molecular mechanism of mitochondrial dysfunction-induced activation of catabolic response in chondrocytes. Using cartilage slices from normal and OA cartilage, we show that mitochondrial membrane potential was lower in OA cartilage which was associated with increased production of mitochondrial superoxide and catabolic genes (IL-6, COX-2, MMP-3,-9,-13 and ADAMTS5). Pharmacological induction of mitochondrial dysfunction in chondrocytes and cartilage explants using CCCP increased the mitochondrial superoxide production and the expression of IL-6, COX-2, MMP-3,-9-13 and ADAMTS5 and cartilage matrix degradation. Mitochondrial dysfunction induced expression of catabolic genes was dependent on JNK/AP1 pathway but not the NFκB pathway. Scavenging of mitochondrial superoxide with MitoTEMPO or pharmacological inhibition of JNK or cFos/cJun blocked the mitochondrial dysfunction-induced expression of the catabolic genes in chondrocytes. We demonstrate here that mitochondrial dysfunction contributes to OA pathogenesis via JNK/AP1 mediated expression of catabolic genes. Our data shows that AP1 could be used as a therapeutic target for OA management.
    Keywords:  Chondrocytes; Inflammation; JNK; Osteoarthritis; Redox; cFos-AP1
  24. iScience. 2020 Oct 23. 23(10): 101564
    Bhaskar S, Sheshadri P, Joseph JP, Potdar C, Prasanna J, Kumar A.
      Studies revealing molecular mechanisms underlying neural specification have majorly focused on the role played by different transcription factors, but less on non-nuclear components. Earlier, we reported mitochondrial superoxide dismutase (SOD2) to be essential for self-renewal and pluripotency of mouse embryonic stem cells (mESCs). In the present study, we found SOD2 to be specifically required for neural lineage, but not the meso- or endoderm specification. Temporally, SOD2 regulated early neural genes, but not the matured genes, by modulating mitochondrial dynamics-specifically by enhancing the mitochondrial fusion protein Mitofusin 2 (MFN2). Bio-complementation strategy further confirmed SOD2 to enhance mitochondrial fusion process independent of its antioxidant activity. Over-expression of SOD2 along with OCT4, but neither alone, transdifferentiated mouse fibroblasts to neural progenitor-like colonies, conclusively proving the neurogenic potential of SOD2. In conclusion, our findings accredit a novel role for SOD2 in early neural lineage specification.
    Keywords:  Developmental Genetics; Developmental Neuroscience; Molecular Genetics
  25. Redox Biol. 2020 Oct 14. pii: S2213-2317(20)30966-6. [Epub ahead of print]37 101761
    Yu W, Wang X, Zhao J, Liu R, Liu J, Wang Z, Peng J, Wu H, Zhang X, Long Z, Kong D, Li W, Hai C.
      Macrophage recruitment and pro-inflammatory differentiation are hallmarks of various diseases, including infection and sepsis. Although studies suggest that mitochondria may regulate macrophage immune responses, it remains unclear whether mitochondrial mass affects macrophage pro-inflammatory differentiation. Here, we found that lipopolysaccharide (LPS)-activated macrophages possess higher mitochondrial mass than resting cells. Therefore, this study aimed to explore the functional role and molecular mechanisms of increased mitochondrial mass in pro-inflammatory differentiated macrophages. Results show that an increase in the mitochondrial mass of macrophages positively correlates with inflammatory cytokine generation in response to LPS. RNA-seq analysis revealed that LPS promotes signal transducers and activators of transcription 2 (Stat2) and dynamin-related protein 1 (Drp1) expression, which are enriched in positive mitochondrial fission regulation. Meanwhile, knockdown or pharmacological inhibition of Drp1 blunts LPS-induced mitochondrial mass increase and pro-inflammatory differentiation. Moreover, Stat2 boosts Drp1 phosphorylation at serine 616, required for Drp1-mediated mitochondrial fission. LPS also causes Stat2-and Drp1-dependent biogenesis, which contributes to the generation of additional mitochondria. However, these mitochondria are profoundly remodeled, displaying fragmented morphology, loose cristae, reduced Δψm, and metabolic programming. Furthermore, these remodeled mitochondria shift their function from ATP synthesis to reactive oxygen species (ROS) production, which drives NFκB-dependent inflammatory cytokine transcription. Interestingly, an increase in mitochondrial mass with constitutively active phosphomimetic mutant of Drp1 (Drp1S616E) boosted pro-inflammatory response in macrophages without LPS stimulation. In vivo, we also demonstrated that Mdivi-1 administration inhibits LPS-induced macrophage pro-inflammatory differentiation. Importantly, we observed Stat2 phosphorylation and Drp1-dependent mitochondrial mass increase in macrophages isolated from LPS-challenged mice. In conclusion, we comprehensively demonstrate that a Stat2-Drp1 dependent mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages. Therefore, targeting the Stat2-Drp1 axis may provide novel therapeutic approaches for treating infection and inflammatory diseases.
    Keywords:  Drp1; Lipopolysaccharide; Mitochondrial mass; Pro-inflammatory macrophage; Reactive oxygen species; Stat2