bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2021‒08‒29
eleven papers selected by
Edmond Chan
Queen’s University, School of Medicine

  1. Cell Rep. 2021 Aug 24. pii: S2211-1247(21)00999-2. [Epub ahead of print]36(8): 109565
      Mitochondria constantly undergo fusion and fission events, referred as mitochondrial dynamics, which determine mitochondrial architecture and bioenergetics. Cultured cell studies demonstrate that mitochondrial dynamics are acutely regulated by phosphorylation of the mitochondrial fission orchestrator dynamin-related protein 1 (Drp1) at S579 or S600. However, the physiological impact and crosstalk of these phosphorylation sites is poorly understood. Here, we describe the functional interrelation between S579 and S600 phosphorylation sites in vivo and their role on mitochondrial remodeling. Mice carrying a homozygous Drp1 S600A knockin (Drp1 KI) mutation display larger mitochondria and enhanced lipid oxidation and respiratory capacities, granting improved glucose tolerance and thermogenic response upon high-fat feeding. Housing mice at thermoneutrality blunts these differences, suggesting a role for the brown adipose tissue in the protection of Drp1 KI mice against metabolic damage. Overall, we demonstrate crosstalk between Drp1 phosphorylation sites and provide evidence that their modulation could be used in the treatment and prevention of metabolic diseases.
    Keywords:  Drp1; brown adipose tissue; insulin resistance; metabolic syndrome; mitochondrial dynamics; mitochondrial respiration; phosphorylation; thermoneutrality
  2. Nat Med. 2021 Aug 23.
      Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis.
  3. Cell Metab. 2021 Aug 17. pii: S1550-4131(21)00365-X. [Epub ahead of print]
      Adipocytes undergo intense energetic stress in obesity resulting in loss of mitochondrial mass and function. We have found that adipocytes respond to mitochondrial stress by rapidly and robustly releasing small extracellular vesicles (sEVs). These sEVs contain respiration-competent, but oxidatively damaged mitochondrial particles, which enter circulation and are taken up by cardiomyocytes, where they trigger a burst of ROS. The result is compensatory antioxidant signaling in the heart that protects cardiomyocytes from acute oxidative stress, consistent with a preconditioning paradigm. As such, a single injection of sEVs from energetically stressed adipocytes limits cardiac ischemia/reperfusion injury in mice. This study provides the first description of functional mitochondrial transfer between tissues and the first vertebrate example of "inter-organ mitohormesis." Thus, these seemingly toxic adipocyte sEVs may provide a physiological avenue of potent cardio-protection against the inevitable lipotoxic or ischemic stresses elicited by obesity.
    Keywords:  adipocyte; cardiovascular disease; diabetes; exosomes; extracellular vesicles; mitochondria; mitochondrial dysfunction; mitohormesis; obesity; stress response
  4. Proc Natl Acad Sci U S A. 2021 Aug 31. pii: e2023909118. [Epub ahead of print]118(35):
      The trace element zinc is essential for many aspects of physiology. The mitochondrion is a major Zn2+ store, and excessive mitochondrial Zn2+ is linked to neurodegeneration. How mitochondria maintain their Zn2+ homeostasis is unknown. Here, we find that the SLC-30A9 transporter localizes on mitochondria and is required for export of Zn2+ from mitochondria in both Caenorhabditis elegans and human cells. Loss of slc-30a9 leads to elevated Zn2+ levels in mitochondria, a severely swollen mitochondrial matrix in many tissues, compromised mitochondrial metabolic function, reductive stress, and induction of the mitochondrial stress response. SLC-30A9 is also essential for organismal fertility and sperm activation in C. elegans, during which Zn2+ exits from mitochondria and acts as an activation signal. In slc-30a9-deficient neurons, misshapen mitochondria show reduced distribution in axons and dendrites, providing a potential mechanism for the Birk-Landau-Perez cerebrorenal syndrome where an SLC30A9 mutation was found.
    Keywords:  Birk–Landau–Perez cerebrorenal syndrome; SLC-30A9; Zn2+ transporters; mitochondria
  5. Curr Opin Chem Biol. 2021 Aug 23. pii: S1367-5931(21)00100-9. [Epub ahead of print]
      The ClpP protease is found across eukaryotic and prokaryotic organisms. It is well-characterized in bacteria where its function is important in maintaining protein homeostasis. Along with its ATPase partners, it has been shown to play critical roles in the regulation of enzymes involved in important cellular pathways. In eukaryotes, ClpP is found within cellular organelles. Proteomic studies have begun to characterize the role of this protease in the mitochondria through its interactions. Here, we discuss the proteomic techniques used to identify its interactors and present an atlas of mitochondrial ClpP substrates. The ClpP substrate pool is extensive and consists of proteins involved in essential mitochondrial processes such as the Krebs cycle, oxidative phosphorylation, translation, fatty acid metabolism, and amino acid metabolism. Discoveries of these associations have begun to illustrate the functional significance of ClpP in human health and disease.
    Keywords:  Cancer; ClpP protease; Mitochondria; Mitochondrial diseases; Parkinson's disease; Protein quality control; Proteolysis; Proteomics; Proteostasis
  6. FEBS J. 2021 Aug 24.
      Coenzyme Q (CoQ, ubiquinone) is the electron-carrying lipid in the mitochondrial electron transport system (ETS). In mammals, it serves as the electron acceptor for nine mitochondrial inner membrane dehydrogenases. These include the NADH-dehydrogenase (complex I, CI) and succinate dehydrogenase (complex II, CII) but also several others that are often omitted in the context of respiratory enzymes: dihydroorotate dehydrogenase, choline dehydrogenase, electron-transferring flavoprotein dehydrogenase, mitochondrial glycerol-3-phosphate dehydrogenase, proline dehydrogenases 1 and 2, and sulfide:quinone oxidoreductase. The metabolic pathways these enzymes are involved in range from amino acid and fatty acid oxidation to nucleotide biosynthesis, methylation, and hydrogen sulfide detoxification, among many others. The CoQ-linked metabolism depends on CoQ re-oxidation by the mitochondrial complex III (cytochrome bc1 complex, CIII). However, the literature is surprisingly limited as for the role of the CoQ-linked metabolism in the pathogenesis of human diseases of oxidative phosphorylation (OXPHOS), in which the CoQ homeostasis is directly or indirectly affected. In this review, we give an introduction to CIII function, and an overview of the pathological consequences of CIII dysfunction in humans and mice and of the CoQ-dependent metabolic processes potentially affected in these pathological states. Finally, we discuss some experimental tools to dissect the various aspects of compromised CoQ oxidation.
    Keywords:  coenzyme Q; complex III; mitochondrial disease; oxidative phosphorylation; ubiquinone
  7. Development. 2021 Apr 01. pii: dev196295. [Epub ahead of print]148(7):
      Mitochondria play a crucial role in spermatogenesis and are regulated by several mitochondrial fusion proteins. However, their functional importance associated with their structure formation and mRNA fate regulation during spermatogenesis remains unclear. Here, we show that mitofusin 2 (MFN2), a mitochondrial fusion protein, interacts with nuage-associated proteins (including MIWI, DDX4, TDRKH and GASZ) in mice. Conditional mutation of Mfn2 in postnatal germ cells results in male sterility due to germ cell developmental defects. Moreover, MFN2 interacts with MFN1, another mitochondrial fusion protein with a high-sequence similarity to MFN2, in testes to facilitate spermatogenesis. Simultaneous mutation of Mfn1 and Mfn2 in testes causes very severe infertile phenotypes. Importantly, we show that MFN2 is enriched in polysome fractions of testes and interacts with MSY2, a germ cell-specific DNA/RNA-binding protein, to control gamete-specific mRNA (such as Spata19) translational activity during spermatogenesis. Collectively, our findings demonstrate that MFN2 interacts with nuage-associated proteins and MSY2 to regulate male germ cell development by controlling several gamete-specific mRNA fates.
    Keywords:  MSY2; Mice; Mitofusins; Nuage proteins; Spermatogenesis
  8. J Cell Biochem. 2021 Aug 25.
      Mitochondria function as an integrated network that moves along the microtubules within cells and changes the morphology through membrane fusion and fission events. Mitofusin (MFN) mediates membrane tethering and subsequent fusion of the mitochondrial outer membrane. Understanding the regulatory mechanisms of MFN function is critical to tackling the pathology related to mitochondrial network imbalance. Here, we reveal a novel inhibitory mechanism of MFN-mediated fusion by mitochondrial Rho GTPase (Miro1) in response to elevated mitochondrial Ca2+ concentration ([Ca2+ ]m ). We showed that elevated [Ca2+ ]m prevents the fusion between mitochondria forming the outer membrane tether by ectopically expressing MFN. Lowering [Ca2+ ]m by treating cells with an inhibitor of mitochondrial calcium uniporter or knocking down Miro1/2 induces more fused networks. Miro1 interacts with MFN as supported by co-immunoprecipitation and protein association identified by proximity labeling proteomics. It suggests that Miro1 functions as a Ca2+ -sensor and inhibits MFN function at elevated [Ca2+ ]m. Miro1 EF-hand mutant has a compromised inhibitory effect, which reiterates Ca2+ -modulated regulation. Dysregulated Ca2+ -handling and mitochondrial network imbalance are highly relevant in the pathology of cancers, cardiovascular, and neurodegenerative diseases. Miro1 functions as a coordinated Ca2+ -responder by pausing mitochondrial transport while reducing network fusion and cooperating with Drp1-mediated fission. It likely prevents the detrimental effect of Ca2+ m overload and facilitates mitophagy. Our finding reveals a novel regulation of mitochondrial network dynamics responding to [Ca2+ ]m through the interplay of Miro1 and MFN. Modulation of Miro1 and MFN interaction is a potential intervention to promote network homeostasis.
    Keywords:  mitochondrial Rho GTPase (Miro); mitochondrial calcium; mitochondrial fusion; mitochondrial network homeostasis; mitofusin (MFN)
  9. Biochem J. 2021 Aug 27. 478(16): 3125-3143
      Mitochondria import about 1000 proteins that are produced as precursors on cytosolic ribosomes. Defects in mitochondrial protein import result in the accumulation of non-imported precursor proteins and proteotoxic stress. The cell is equipped with different quality control mechanisms to monitor protein transport into mitochondria. First, molecular chaperones guide unfolded proteins to mitochondria and deliver non-imported proteins to proteasomal degradation. Second, quality control factors remove translocation stalled precursor proteins from protein translocases. Third, protein translocases monitor protein sorting to mitochondrial subcompartments. Fourth, AAA proteases of the mitochondrial subcompartments remove mislocalized or unassembled proteins. Finally, impaired efficiency of protein transport is an important sensor for mitochondrial dysfunction and causes the induction of cellular stress responses, which could eventually result in the removal of the defective mitochondria by mitophagy. In this review, we summarize our current understanding of quality control mechanisms that govern mitochondrial protein transport.
    Keywords:  TIM23 complex; TOM complex; mitochondria; protein sorting; protein transport
  10. STAR Protoc. 2021 Sep 17. 2(3): 100735
      Depending on metabolic requirements, skeletal muscle mitochondria integrate O2 consumption and ATP production with lipid, glucose, or amino acid metabolism. Free fatty acids (FFAs) are the main source of energy during rest and mild-intensity exercise. We present a detailed protocol for measuring FFA-β-oxidation coupled with O2 respiration by a Clark-type electrode in isolated mitochondria from mouse soleus oxidative muscle. We optimized the procedure, including buffer composition, protease treatment, and quantifiable parameters (P/O, Phosphate/Oxygen Ratio; OCR, Oxygen Consumption Rate; RCR,Respiration Control Rate; OSR, Oligomycin Sensitive Respiration). For complete details on the use and execution of this protocol, please refer to Sanchez-Gonzalez et al. (2020).
    Keywords:  cell biology; cell isolation; cell membrane; cell separation/fractionation; metabolism