bims-mecmid Biomed News
on Membrane communication in mitochondrial dynamics
Issue of 2022–01–23
seven papers selected by
Mauricio Cardenas Rodriguez, University of Padova
  1. Enrichment of the exocytosis protein STX4 in skeletal muscle remediates peripheral insulin resistance and alters mitochondrial dynamics via Drp1.
  2. Mitochondrial Membrane Remodeling.
  3. Mitochondrial fusion, fission and mitophagy in cardiac diseases: challenges and therapeutic opportunities.
  4. OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling.
  5. MITOCHONDRIA: Mitochondrial dynamics in the regulation of stem cells.
  6. Uncovering the important role of mitochondrial dynamics in oogenesis: impact on fertility and metabolic disorder transmission.
  7. Architects of their own environment: How membrane proteins shape the Gram-negative cell envelope.
  1. Nat Commun. 2022 Jan 20. 13(1): 424
    Enrichment of the exocytosis protein STX4 in skeletal muscle remediates peripheral insulin resistance and alters mitochondrial dynamics via Drp1.
    Karla E Merz, Jinhee Hwang, Chunxue Zhou, Rajakrishnan Veluthakal, Erika M McCown, Angelica Hamilton, Eunjin Oh, Wenting Dai, Patrick T Fueger, Lei Jiang, Janice M Huss, Debbie C Thurmond.
      Mitochondrial dysfunction is implicated in skeletal muscle insulin resistance. Syntaxin 4 (STX4) levels are reduced in human diabetic skeletal muscle, and global transgenic enrichment of STX4 expression improves insulin sensitivity in mice. Here, we show that transgenic skeletal muscle-specific STX4 enrichment (skmSTX4tg) in mice reverses established insulin resistance and improves mitochondrial function in the context of diabetogenic stress. Specifically, skmSTX4tg reversed insulin resistance caused by high-fat diet (HFD) without altering body weight or food consumption. Electron microscopy of wild-type mouse muscle revealed STX4 localisation at or proximal to the mitochondrial membrane. STX4 enrichment prevented HFD-induced mitochondrial fragmentation and dysfunction through a mechanism involving STX4-Drp1 interaction and elevated AMPK-mediated phosphorylation at Drp1 S637, which favors fusion. Our findings challenge the dogma that STX4 acts solely at the plasma membrane, revealing that STX4 localises at/proximal to and regulates the function of mitochondria in muscle. These results establish skeletal muscle STX4 enrichment as a candidate therapeutic strategy to reverse peripheral insulin resistance.
    DOI:  https://doi.org/10.1038/s41467-022-28061-w
  2. Front Bioeng Biotechnol. 2021 ;9 786806
    Mitochondrial Membrane Remodeling.
    Ziyun Yang, Liang Wang, Cheng Yang, Shiming Pu, Ziqi Guo, Qiong Wu, Zuping Zhou, Hongxia Zhao.
      Mitochondria are key regulators of many important cellular processes and their dysfunction has been implicated in a large number of human disorders. Importantly, mitochondrial function is tightly linked to their ultrastructure, which possesses an intricate membrane architecture defining specific submitochondrial compartments. In particular, the mitochondrial inner membrane is highly folded into membrane invaginations that are essential for oxidative phosphorylation. Furthermore, mitochondrial membranes are highly dynamic and undergo constant membrane remodeling during mitochondrial fusion and fission. It has remained enigmatic how these membrane curvatures are generated and maintained, and specific factors involved in these processes are largely unknown. This review focuses on the current understanding of the molecular mechanism of mitochondrial membrane architectural organization and factors critical for mitochondrial morphogenesis, as well as their functional link to human diseases.
    Keywords:  Mitochondrial disease; cardiolipin; crista junctions; cristae; membrane curvature; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.3389/fbioe.2021.786806
  3. Antioxid Redox Signal. 2022 Jan 19.
    Mitochondrial fusion, fission and mitophagy in cardiac diseases: challenges and therapeutic opportunities.
    Débora da Luz Scheffer, Adriana Ann Garcia, Lucia Lee, Daria Mochly-Rosen, Julio Cesar Batista Ferreira.
       SIGNIFICANCE: Mitochondria play a critical role in the physiology of the heart by controlling cardiac metabolism, function, and remodeling. Accumulation of fragmented and damaged mitochondria is a hallmark of cardiac diseases. Recent Advances: Disruption of quality control systems that maintain mitochondrial number, size, and shape through fission-fusion balance and mitophagy results in dysfunctional mitochondria, defective mitochondrial segregation, impaired cardiac bioenergetics, and excessive oxidative stress.
    CRITICAL ISSUES: Pharmacological tools that improve the cardiac pool of healthy mitochondria through inhibition of excessive mitochondrial fission, boosting mitochondrial fusion, or increasing the clearance of damaged mitochondria have emerged as promising approaches to improve the prognosis of heart diseases.
    FUTURE DIRECTIONS: There is a reasonable amount of pre-clinical evidence supporting the effectiveness of molecules targeting mitochondrial fission and fusion to treat cardiac diseases. The current and future challenges are turning these lead molecules into treatments. Clinical studies focusing on acute (i.e., myocardial infarction) and chronic (i.e., heart failure) cardiac diseases are needed to validate the effectiveness of such strategies in improving mitochondrial morphology, metabolism, and cardiac function.
    DOI:  https://doi.org/10.1089/ars.2021.0145
  4. Front Cell Dev Biol. 2021 ;9 774108
    OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling.
    Benjamín Cartes-Saavedra, Josefa Macuada, Daniel Lagos, Duxan Arancibia, María E Andrés, Patrick Yu-Wai-Man, György Hajnóczky, Verónica Eisner.
      Autosomal Dominant Optic Atrophy (ADOA), a disease that causes blindness and other neurological disorders, is linked to OPA1 mutations. OPA1, dependent on its GTPase and GED domains, governs inner mitochondrial membrane (IMM) fusion and cristae organization, which are central to oxidative metabolism. Mitochondrial dynamics and IMM organization have also been implicated in Ca2+ homeostasis and signaling but the specific involvements of OPA1 in Ca2+ dynamics remain to be established. Here we studied the possible outcomes of OPA1 and its ADOA-linked mutations in Ca2+ homeostasis using rescue and overexpression strategies in Opa1-deficient and wild-type murine embryonic fibroblasts (MEFs), respectively and in human ADOA-derived fibroblasts. MEFs lacking Opa1 required less Ca2+ mobilization from the endoplasmic reticulum (ER) to induce a mitochondrial matrix [Ca2+] rise ([Ca2+]mito). This was associated with closer ER-mitochondria contacts and no significant changes in the mitochondrial calcium uniporter complex. Patient cells carrying OPA1 GTPase or GED domain mutations also exhibited altered Ca2+ homeostasis, and the mutations associated with lower OPA1 levels displayed closer ER-mitochondria gaps. Furthermore, in Opa1 -/- MEF background, we found that acute expression of OPA1 GTPase mutants but no GED mutants, partially restored cytosolic [Ca2+] ([Ca2+]cyto) needed for a prompt [Ca2+]mito rise. Finally, OPA1 mutants' overexpression in WT MEFs disrupted Ca2+ homeostasis, partially recapitulating the observations in ADOA patient cells. Thus, OPA1 modulates functional ER-mitochondria coupling likely through the OPA1 GED domain in Opa1 -/- MEFs. However, the co-existence of WT and mutant forms of OPA1 in patients promotes an imbalance of Ca2+ homeostasis without a domain-specific effect, likely contributing to the overall ADOA progress.
    Keywords:  ADOA; OPA1; calcium; endoplasmic reticulum; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2021.774108
  5. Int J Biochem Cell Biol. 2022 Jan 18. pii: S1357-2725(22)00003-6. [Epub ahead of print] 106158
    MITOCHONDRIA: Mitochondrial dynamics in the regulation of stem cells.
    Steven Wade, Mireille Khacho.
      Mitochondria are considered the metabolic hubs within a cell. These organelles are highly dynamic and continuously undergo cycles of fission and fusion events. The balance in the dynamic state of mitochondria is critical for maintaining key physiological events within cells. Here we discuss the emerging role of mitochondrial dynamics in regulating stem cell function and highlight the crosstalk between mitochondrial shape and intracellular signaling cascades within the context of stem cells.
    DOI:  https://doi.org/10.1016/j.biocel.2022.106158
  6. Biophys Rev. 2021 Dec;13(6): 967-981
    Uncovering the important role of mitochondrial dynamics in oogenesis: impact on fertility and metabolic disorder transmission.
    Marcos Roberto Chiaratti.
      Oocyte health is tightly tied to mitochondria given their role in energy production, metabolite supply, calcium (Ca2+) buffering, and cell death regulation, among others. In turn, mitochondrial function strongly relies on these organelle dynamics once cyclic events of fusion and fission (division) are required for mitochondrial turnover, positioning, content homogenization, metabolic flexibility, interaction with subcellular compartments, etc. Importantly, during oogenesis, mitochondria change their architecture from an "orthodox" elongated shape characterized by the presence of numerous transversely oriented cristae to a round-to-oval morphology containing arched and concentrically arranged cristae. This, along with evidence showing that mitochondrial function is kept quiescent during most part of oocyte development, suggests an important role of mitochondrial dynamics in oogenesis. To investigate this, recent works have downregulated/upregulated in oocytes the expression of key effectors of mitochondrial dynamics, including mitofusins 1 (MFN1) and 2 (MFN2) and the dynamin-related protein 1 (DRP1). As a result, both MFN1 and DRP1 were found to be essential to oogenesis and fertility, while MFN2 deletion led to offspring with increased weight gain and glucose intolerance. Curiously, neither MFN1/MFN2 deficiency nor DRP1 overexpression enhanced mitochondrial fragmentation, indicating that mitochondrial size is strictly regulated in oocytes. Therefore, the present work seeks to discuss the role of mitochondria in supporting oogenesis as well as recent findings connecting defective mitochondrial dynamics in oocytes with infertility and transmission of metabolic disorders.
    Keywords:  DRP1; Endoplasmic reticulum; MFN1; MFN2; Mitochondria; Oocyte
    DOI:  https://doi.org/10.1007/s12551-021-00891-w
  7. Adv Protein Chem Struct Biol. 2022 ;pii: S1876-1623(21)00081-X. [Epub ahead of print]128 1-34
    Architects of their own environment: How membrane proteins shape the Gram-negative cell envelope.
    Johannes Thoma, Björn M Burmann.
      Gram-negative bacteria are surrounded by a complex multilayered cell envelope, consisting of an inner and an outer membrane, and separated by the aqueous periplasm, which contains a thin peptidoglycan cell wall. These bacteria employ an arsenal of highly specialized membrane protein machineries to ensure the correct assembly and maintenance of the membranes forming the cell envelope. Here, we review the diverse protein systems, which perform these functions in Escherichia coli, such as the folding and insertion of membrane proteins, the transport of lipoproteins and lipopolysaccharide within the cell envelope, the targeting of phospholipids, and the regulation of mistargeted envelope components. Some of these protein machineries have been known for a long time, yet still hold surprises. Others have only recently been described and some are still missing pieces or yet remain to be discovered.
    Keywords:  Cell envelope; Cell membrane; Gram-negative bacteria; Membrane biogenesis; Membrane homeostasis; Membrane proteins; Outer membrane; Protein folding
    DOI:  https://doi.org/10.1016/bs.apcsb.2021.10.001
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