bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2020‒10‒11
eighteen papers selected by
Edmond Chan
Queen’s University, School of Medicine

  1. Cell. 2020 Sep 24. pii: S0092-8674(20)31091-6. [Epub ahead of print]
    Daw CC, Ramachandran K, Enslow BT, Maity S, Bursic B, Novello MJ, Rubannelsonkumar CS, Mashal AH, Ravichandran J, Bakewell TM, Wang W, Li K, Madaris TR, Shannon CE, Norton L, Kandala S, Caplan J, Srikantan S, Stathopulos PB, Reeves WB, Madesh M.
      Mg2+ is the most abundant divalent cation in metazoans and an essential cofactor for ATP, nucleic acids, and countless metabolic enzymes. To understand how the spatio-temporal dynamics of intracellular Mg2+ (iMg2+) are integrated into cellular signaling, we implemented a comprehensive screen to discover regulators of iMg2+ dynamics. Lactate emerged as an activator of rapid release of Mg2+ from endoplasmic reticulum (ER) stores, which facilitates mitochondrial Mg2+ (mMg2+) uptake in multiple cell types. We demonstrate that this process is remarkably temperature sensitive and mediated through intracellular but not extracellular signals. The ER-mitochondrial Mg2+ dynamics is selectively stimulated by L-lactate. Further, we show that lactate-mediated mMg2+ entry is facilitated by Mrs2, and point mutations in the intermembrane space loop limits mMg2+ uptake. Intriguingly, suppression of mMg2+ surge alleviates inflammation-induced multi-organ failure. Together, these findings reveal that lactate mobilizes iMg2+ and links the mMg2+ transport machinery with major metabolic feedback circuits and mitochondrial bioenergetics.
    Keywords:  Mrs2; calcium; cancer; channel; endoplasmic reticulum; inflammation; lactate; magnesium; metabolism; mitochondria
  2. Nat Commun. 2020 10 07. 11(1): 5052
    May AI, Prescott M, Ohsumi Y.
      The mechanism and function of autophagy as a highly-conserved bulk degradation pathway are well studied, but the physiological role of autophagy remains poorly understood. We show that autophagy is involved in the adaptation of Saccharomyces cerevisiae to respiratory growth through its recycling of serine. On respiratory media, growth onset, mitochondrial initiator tRNA modification and mitochondrial protein expression are delayed in autophagy defective cells, suggesting that mitochondrial one-carbon metabolism is perturbed in these cells. The supplementation of serine, which is a key one-carbon metabolite, is able to restore mitochondrial protein expression and alleviate delayed respiratory growth. These results indicate that autophagy-derived serine feeds into mitochondrial one-carbon metabolism, supporting the initiation of mitochondrial protein synthesis and allowing rapid adaptation to respiratory growth.
  3. Nat Commun. 2020 10 05. 11(1): 4983
    Kang JH, Katsikis G, Li Z, Sapp KM, Stockslager MA, Lim D, Vander Heiden MG, Yaffe MB, Manalis SR, Miettinen TP.
      The energetic demands of a cell are believed to increase during mitosis, but the rates of ATP synthesis and consumption during mitosis have not been quantified. Here, we monitor mitochondrial membrane potential of single lymphocytic leukemia cells and demonstrate that mitochondria hyperpolarize from the G2/M transition until the metaphase-anaphase transition. This hyperpolarization was dependent on cyclin-dependent kinase 1 (CDK1) activity. By using an electrical circuit model of mitochondria, we quantify mitochondrial ATP synthesis rates in mitosis from the single-cell time-dynamics of mitochondrial membrane potential. We find that mitochondrial ATP synthesis decreases by approximately 50% during early mitosis and increases back to G2 levels during cytokinesis. Consistently, ATP levels and ATP synthesis are lower in mitosis than in G2 in synchronized cell populations. Overall, our results provide insights into mitotic bioenergetics and suggest that cell division is not a highly energy demanding process.
  4. Nat Metab. 2020 Oct 05.
    Li S, Xiong GJ, Huang N, Sheng ZH.
      Mitochondria supply ATP essential for synaptic transmission. Neurons face exceptional challenges in maintaining energy homoeostasis at synapses. Regulation of mitochondrial trafficking and anchoring is critical for neurons to meet increased energy consumption during sustained synaptic activity. However, mechanisms recruiting and retaining presynaptic mitochondria in sensing synaptic ATP levels remain elusive. Here we reveal an energy signalling axis that controls presynaptic mitochondrial maintenance. Activity-induced presynaptic energy deficits can be rescued by recruiting mitochondria through the AMP-activated protein kinase (AMPK)-p21-activated kinase (PAK) energy signalling pathway. Synaptic activity induces AMPK activation within axonal compartments and AMPK-PAK signalling triggers phosphorylation of myosin VI, which drives mitochondrial recruitment and syntaphilin-mediated anchoring on presynaptic filamentous actin. This pathway maintains presynaptic energy supply and calcium clearance during intensive synaptic activity. Disrupting this signalling cross-talk triggers local energy deficits and intracellular calcium build-up, leading to impaired synaptic efficacy during trains of stimulation and reduced recovery from synaptic depression after prolonged synaptic activity. Our study reveals a mechanistic cross-talk between energy sensing and mitochondria anchoring to maintain presynaptic metabolism, thus fine-tuning short-term synaptic plasticity and prolonged synaptic efficacy.
  5. Mol Cell. 2020 Sep 29. pii: S1097-2765(20)30648-1. [Epub ahead of print]
    Cai Z, Li CF, Han F, Liu C, Zhang A, Hsu CC, Peng D, Zhang X, Jin G, Rezaeian AH, Wang G, Zhang W, Pan BS, Wang CY, Wang YH, Wu SY, Yang SC, Hsu FC, D'Agostino RB, Furdui CM, Kucera GL, Parks JS, Chilton FH, Huang CY, Tsai FJ, Pasche B, Watabe K, Lin HK.
      Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.
    Keywords:  AMPK; PDHA; TCA cycle; breast cancer; cancer metastasis; metabolic stress
  6. iScience. 2020 Sep 29. 101631
    Burtscher J, Cappellano G, Omori A, Koshiba T, Millet GP.
      The pathophysiology, immune reaction, differential vulnerability of different population groups and viral host immune system evasion strategies of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection are not yet well understood. Here, we reviewed the multitude of known strategies of coronaviruses and other viruses to usurp mitochondria-associated mechanisms involved in the host innate immune response and put them in context with the current knowledge on SARS-CoV-2. We argue that maintenance of mitochondrial integrity is essential for adequate innate immune system responses and to blunt mitochondrial modulation by SARS-CoV-2. Mitochondrial health thus may determine differential vulnerabilities to SARS-CoV-2 infection rendering markers of mitochondrial functions promising potential biomarkers for SARS-CoV-2 infection risk and severity of outcome. Current knowledge gaps on our understanding of mitochondrial involvement in SARS-CoV-2 infection, life-style and pharmacological strategies to improve mitochondrial integrity and potential reciprocal interactions with chronic and age-related diseases, e.g. Parkinson's Disease, are pointed out.
  7. Nat Immunol. 2020 Oct 05.
    Yu YR, Imrichova H, Wang H, Chao T, Xiao Z, Gao M, Rincon-Restrepo M, Franco F, Genolet R, Cheng WC, Jandus C, Coukos G, Jiang YF, Locasale JW, Zippelius A, Liu PS, Tang L, Bock C, Vannini N, Ho PC.
      The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.
  8. Annu Rev Cell Dev Biol. 2020 Oct 06. 36 265-289
    Moehlman AT, Youle RJ.
      Maintaining mitochondrial health is essential for the survival and function of eukaryotic organisms. Misfunctioning mitochondria activate stress-responsive pathways to restore mitochondrial network homeostasis, remove damaged or toxic proteins, and eliminate damaged organelles via selective autophagy of mitochondria, a process termed mitophagy. Failure of these quality control pathways is implicated in the pathogenesis of Parkinson's disease and other neurodegenerative diseases. Impairment of mitochondrial quality control has been demonstrated to activate innate immune pathways, including inflammasome-mediated signaling and the antiviral cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)-regulated interferon response. Immune system malfunction is a common hallmark in many neurodegenerative diseases; however, whether inflammation suppresses or exacerbates disease pathology is still unclear. The goal of this review is to provide a historical overview of the field, describe mechanisms of mitochondrial quality control, and highlight recent advances on the emerging role of mitochondria in innate immunity and inflammation.
    Keywords:  immunity; inflammation; mitochondria; mitophagy; neurodegeneration
  9. Cell Metab. 2020 Oct 06. pii: S1550-4131(20)30419-8. [Epub ahead of print]32(4): 507-509
    Procaccini C, Matarese G.
      Although a crucial role for mitochondrial metabolism in controlling T regulatory (Treg) cell function has been recognized, its contribution during autoimmunity has not yet been fully elucidated. In this issue of Cell Metabolism, Alissafi and colleagues demonstrate that during autoimmunity, Treg cell functional alterations associate with mitochondrial oxidative stress, dysfunctional mitophagy, and enhanced DNA damage response, culminating with their cell death.
  10. Cell Metab. 2020 Oct 06. pii: S1550-4131(20)30486-1. [Epub ahead of print]
    Song JD, Alves TC, Befroy DE, Perry RJ, Mason GF, Zhang XM, Munk A, Zhang Y, Zhang D, Cline GW, Rothman DL, Petersen KF, Shulman GI.
      Alterations in muscle mitochondrial substrate preference have been postulated to play a major role in the pathogenesis of muscle insulin resistance. In order to examine this hypothesis, we assessed the ratio of mitochondrial pyruvate oxidation (VPDH) to rates of mitochondrial citrate synthase flux (VCS) in muscle. Contrary to this hypothesis, we found that high-fat-diet (HFD)-fed insulin-resistant rats did not manifest altered muscle substrate preference (VPDH/VCS) in soleus or quadriceps muscles in the fasting state. Furthermore, hyperinsulinemic-euglycemic (HE) clamps increased VPDH/VCS in both muscles in normal and insulin-resistant rats. We then examined the muscle VPDH/VCS flux in insulin-sensitive and insulin-resistant humans and found similar relative rates of VPDH/VCS, following an overnight fast (∼20%), and similar increases in VPDH/VCS fluxes during a HE clamp. Altogether, these findings demonstrate that alterations in mitochondrial substrate preference are not an essential step in the pathogenesis of muscle insulin resistance.
    Keywords:  Randle Cycle; citrate synthase; glucose oxidation; insulin resistance; metabolic flux; metabolic inflexibility; mitochondria; muscle metabolism; pyruvate dehydrogenase; respiratory quotient
  11. Cell Rep. 2020 Oct 06. pii: S2211-1247(20)31220-1. [Epub ahead of print]33(1): 108231
    Hollinshead KER, Parker SJ, Eapen VV, Encarnacion-Rosado J, Sohn A, Oncu T, Cammer M, Mancias JD, Kimmelman AC.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive fibrosis and hypovascularization, resulting in significant intratumoral hypoxia (low oxygen) that contributes to its aggressiveness, therapeutic resistance, and high mortality. Despite oxygen being a fundamental requirement for many cellular and metabolic processes, and the severity of hypoxia in PDAC, the impact of oxygen deprivation on PDAC biology is poorly understood. Investigating how PDAC cells survive in the near absence of oxygen, we find that PDAC cell lines grow robustly in oxygen tensions down to 0.1%, maintaining mitochondrial morphology, membrane potential, and the oxidative metabolic activity required for the synthesis of key metabolites for proliferation. Disrupting electron transfer efficiency by targeting mitochondrial respiratory supercomplex assembly specifically affects hypoxic PDAC proliferation, metabolism, and in vivo tumor growth. Collectively, our results identify a mechanism that enables PDAC cells to thrive in severe, oxygen-limited microenvironments.
    Keywords:  COX7A2L; aspartate; electron transport chain; hypoxia; pancreatic cancer; respiration; supercomplexes
  12. J Biol Chem. 2020 Oct 07. pii: jbc.RA120.014253. [Epub ahead of print]
    Manjunath LE, Singh A, Sahoo S, Mishra A, Padmarajan J, Basavaraju CG, Eswarappa SM.
      Stop codon readthrough (SCR) is a process of continuation of translation beyond a stop codon. This phenomenon, which occurs only in certain mRNAs under specific conditions, leads to a longer isoform with properties different from that of the canonical isoform. MTCH2, which encodes a mitochondrial protein that regulates mitochondrial metabolism, was selected as a potential readthrough candidate based on evolutionary conservation observed in the proximal region of its 3'UTR. Here, we demonstrate translational readthrough across two evolutionarily conserved, in-frame stop codons of MTCH2 using luminescence- and fluorescence-based assays, and by analyzing ribosome-profiling and mass-spectrometry data. This phenomenon generates two isoforms, MTCH2x and MTCH2xx (single- and double-SCR products, respectively), in addition to the canonical isoform MTCH2, from the same mRNA. Our experiments revealed that a cis-acting 12-nucleotide sequence in the proximal 3'UTR of MTCH2 is the necessary signal for SCR. Functional characterization showed that MTCH2 and MTCH2x were localized to mitochondria with a long half-life (> 36 h). However, MTCH2xx was found predominantly in the cytoplasm. This mislocalization and its unique C-terminus led to increased degradation, as shown by greatly reduced half-life (< 1 h). MTCH2 readthrough-deficient cells, generated using CRISPR-Cas9, showed increased MTCH2 expression and, consistent with this, decreased mitochondrial membrane potential. Thus, double-SCR of MTCH2 regulates its own expression levels contributing towards the maintenance of normal mitochondrial membrane potential.
    Keywords:  mRNA; mitochondrial membrane potential; protein degradation; ribosome; translation control
  13. Cancers (Basel). 2020 Oct 01. pii: E2845. [Epub ahead of print]12(10):
    Chang YJ, Chen KW, Chen L.
      Increased ROS proto-oncogene 1 (ROS1) expression has been implicated in the invasiveness of human oral squamous cell carcinoma (OSCC). The cellular distribution of ROS1 has long-been assumed at the plasma membrane. However, a previous work reported a differential cellular distribution of mutant ROS1 derived from chromosomal translocation, resulting in increased carcinogenesis. We thus hypothesized that cellular distribution of upregulated ROS1 in OSCC may correlate with invasiveness. We found that ROS1 can localize to mitochondria in the highly invasive OSCC and identified a mitochondria-targeting signal sequence in ROS1. We also demonstrated that ROS1 targeting to mitochondria is required for mitochondrial fission phenotype in the highly invasive OSCC cells. OSCC cells expressing high levels of ROS1 consumed more oxygen and had increased levels of cellular ATP levels. Our results also revealed that ROS1 regulates mitochondrial biogenesis and cellular metabolic plasticity. Together, these findings demonstrate that ROS1 targeting to mitochondria enhances OSCC invasion through regulating mitochondrial morphogenesis and cellular respiratory.
    Keywords:  ROS1 oncogene; mitochondrial fission; mitochondrial respiratory capacity; oral cancer
  14. Br J Pharmacol. 2020 Oct 10.
    Strobbe D, Pecorari R, Conte O, Minutolo A, Hendriks CMM, Wiezorek S, Faccenda D, Abeti R, Montesano C, Bolm C, Campanella M.
      BACKGROUND AND PURPOSE: The mitochondrial enzyme F1 Fo -ATPsynthase is core to cellular homeostasis. Its function is compromised in acute pathologies such as ischemia, as well as in those caused by long-term acquired metabolic dysfunctions. This makes the F1 Fo -ATPsynthase an important target for therapeutic interventions in diseases such as cancer. Despite this, pharmacological tools to selectively inhibit the hydrolysis of ATP by the F1 Fo-ATPase without affecting its synthesis remain scarce. Here, we report the synthesis and in vitro characterization of the NH-Sulfoximine (NHS) that is the suxolfimine analogue of the compound BTB-06584 (BTB) which we characterized as F1 Fo-ATPase inhibitor.EXPERIMENTAL APPROACH: The chemical structure of BTB worked as template to gain the sulfoximine analogue NHS whose activity was assessed in human neuroblastoma SH-SY5Y cell line. In this we profiled ATP levels (i), cell viability (ii), and mitochondrial quality control mechanisms (iii) when it was given alone or in combination with either the glucose analogue 2-deoxyglucose (2-DG) or the chemotherapeutic agent etoposide (Eto).
    KEY RESULTS: NHS selectively blocks the consumption of ATP by mitochondria, independently of the F1 Fo -ATPase Inhibitory Factor 1 (IF1 ), leading to a subtle cytoxicity associated with the concomitant engagement of autophagy and impairment of cell viability.
    CONCLUSION AND IMPLICATIONS: This study describes a new pharmacological inhibitor of the mitochondrial F1 Fo -ATPase that is able, by selectively blocking ATP hydrolysis, to perturb the bioenergetic homeostasis of cancer cells leading to a non-apoptotic type of cell death.
  15. Autophagy. 2020 Oct 09.
    Manganelli V, Matarrese P, Antonioli M, Gambardella L, Vescovo T, Gretzmeier C, Longo A, Capozzi A, Recalchi S, Riitano G, Misasi R, Dengjel J, Malorni W, Fimia GM, Sorice M, Garofalo T.
      Mitochondria-associated membranes (MAMs) are essential communication subdomains of the endoplasmic reticulum (ER) that interact with mitochondria. We previously demonstrated that, upon macroautophagy/autophagy induction, AMBRA1 is recruited to the BECN1 complex and relocalizes to MAMs, where it regulates autophagy by interacting with raft-like components. ERLIN1 is an endoplasmic reticulum lipid raft protein of the prohibitin family. However, little is known about its association with the MAM interface and its involvement in autophagic initiation. In this study, we investigated ERLIN1 association with MAM raft-like microdomains and its interaction with AMBRA1 in the regulation of the autophagic process. We show that ERLIN1 interacts with AMBRA1 at MAM raft-like microdomains, which represents an essential condition for autophagosome formation upon nutrient starvation, as demonstrated by knocking down ERLIN1 gene expression. Moreover, this interaction depends on the "integrity" of key molecules, such as ganglioside GD3 and MFN2. Indeed, knocking down ST8SIA1/GD3-synthase or MFN2 expression impairs AMBRA1-ERLIN1 interaction at the MAM level and hinders autophagy. In conclusion, AMBRA1-ERLIN1 interaction within MAM raft-like microdomains appears to be pivotal in promoting the formation of autophagosomes.
    Keywords:  AMBRA1; ERLIN1; autophagy; lipid rafts; mitochondria associated membranes
  16. Trends Cell Biol. 2020 Sep 30. pii: S0962-8924(20)30173-2. [Epub ahead of print]
    Pizzuto M, Pelegrin P.
      Cardiolipin (CL) is a tetra-acylated diphosphatidylglycerol lipid. In physiological conditions, CL presents unsaturated chains and is located in the inner mitochondria membrane (IMM). Dead signals, infection, or disease may change the level of CL saturation and oxidation and cause its translocation to the cytosolic side of the outer mitochondrial membrane (OMM), affecting mitochondrial function and the inflammatory response. In this review, we summarize the emerging proapoptotic, pro-, and anti-inflammatory functions of cytosolic-exposed CL and how they are regulated by CL chain saturation and oxidation. We underline how the unique dimeric phospholipid structure confers peculiar properties on CL in the regulation of cell death and immune system proteins, such as the Nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3), caspases (Casp), and Toll-like receptor 4 (TLR4). We also provide an overview of the human diseases in which CL deficiency or modification are implicated and of the use of exogenous unsaturated CL (uCL) as a novel therapeutic approach.
  17. Curr Alzheimer Res. 2020 Oct 06.
    Pakpian N, Phopin K, Kitidee K, Govitrapong P, Wongchitrat P.
      BACKGROUND: Mitochondrial dysfunction is a pathological feature that manifests early in the brains of patients with Alzheimer's disease (AD). The disruption of mitochondrial dynamics contributes to mitochondrial morphological and functional impairments. Our previous study demonstrated that the expression of genes involved in amyloid beta generation was altered in the peripheral blood of AD patients.OBJECTIVE: The aim of this study was to further investigate the relative levels of mitochondrial genes involved in mitochondrial dynamics, including mitochondrial fission and fusion, and mitophagy in peripheral blood samples from patients with AD compared to healthy controls.
    METHODS: The mRNA levels were analyzed by real-time polymerase chain reaction. Gene expression profiles were assessed in relation to cognitive performance.
    RESULT: Significant changes were observed in the mRNA expression levels of fission-related genes; Fission1 (FIS1) levels in AD subjects were significantly higher than those in healthy controls, whereas Dynamin-related protein 1 (DRP1) expression was significantly lower in AD subjects. The levels of the mitophagy-related genes, PTEN-induced kinase 1 (PINK1) and microtubule-associated protein 1 light chain 3 (LC3), were significantly increased in AD subjects and elderly controls compared to healthy young controls. The mRNA levels of Parkin (PARK2) were significantly decreased in AD. Correlations were found between the expression levels of FIS1, DRP1 and PARK2 and cognitive performance scores.
    CONCLUSION: Alterations in mitochondrial dynamics in the blood may reflect impairments in mitochondrial functions in the central and peripheral tissues of AD patients. Mitochondrial fission, together with mitophagy gene profiles, might be potential considerations for the future development of blood-based biomarkers for AD.
    Keywords:  Alzheimer's disease; DRP1; FIS1; mitochondrial dynamics; mitophagy
  18. Aging Dis. 2020 Oct;11(5): 1260-1275
    Li W, Kui L, Demetrios T, Gong X, Tang M.
      Mitochondria are classically known to be cellular energy producers. Given the high-energy demanding nature of neurons in the brain, it is essential that the mitochondrial pool remains healthy and provides a continuous and efficient supply of energy. However, mitochondrial dysfunction is inevitable in aging and neurodegenerative diseases. In Alzheimer's disease (AD), neurons experience unbalanced homeostasis like damaged mitochondrial biogenesis and defective mitophagy, with the latter promoting the disease-defining amyloid β (Aβ) and p-Tau pathologies impaired mitophagy contributes to inflammation and the aggregation of Aβ and p-Tau-containing neurotoxic proteins. Interventions that restore defective mitophagy may, therefore, alleviate AD symptoms, pointing out the possibility of a novel therapy. This review aims to illustrate mitochondrial biology with a focus on mitophagy and propose strategies to treat AD while maintaining mitochondrial homeostasis.
    Keywords:  Alzheimer’s disease; NAD+; mitochondria dysfunction; mitophagy