bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022‒06‒12
seven papers selected by
Avinash N. Mukkala
University of Toronto

  1. Autophagy. 2022 Jun 05. 1-2
      The protein TRIM5 is under intensive investigation related to its roles in antiviral defense, yet its underlying mechanisms of action remain elusive. In our study, we performed an unbiased identification of TRIM5-interacting partners and found proteins participating in a wide variety of cellular functions. We utilized this proteomics data set to uncover a role for TRIM5 in mitophagy, a mitochondrial quality control system that is impaired in multiple human diseases. Mitochondrial damage triggers the recruitment of TRIM5 to ER-mitochondria contact sites where TRIM5 colocalizes with markers of autophagosome biogenesis. Cells lacking TRIM5 are unable to carry out PRKN-dependent and PRKN-independent mitophagy pathways. TRIM5 knockout cells show reduced mitochondrial function and uncontrolled immune activation in response to mitochondrial damage; phenotypes consistent with a requirement for TRIM5 in mitophagy. Mechanistically, we found that TRIM5 is required for the recruitment of the autophagy initiation machinery to damaged mitochondria, where TRIM5 acts as a scaffold promoting interactions between protein markers of mitochondrial damage and the autophagy initiation machinery.
    Keywords:  APEX2; HIV-1; TRIM5α; autophagy; inflammation; mitochondria; mitophagy; restriction factor; tripartite-motif
  2. Neurosci Res. 2022 Jun 07. pii: S0168-0102(22)00172-9. [Epub ahead of print]
      BAX is a Bcl-2 family protein acting on apoptosis. It also promotes mitochondrial fusion by interacting with the mitochondrial fusion protein Mitofusin (Mfn1 and Mfn2). Neuronal mitochondria are important for the development and modification of dendritic spines, which are subcellular compartments accommodating excitatory synapses in postsynaptic neurons. The abundance of dendritic mitochondria influences dendritic spine development. Mitochondrial fusion is essential for mitochondrial homeostasis. Here, we show that in the hippocampal neuron of BAX knockout mice, mitochondrial fusion is impaired, leading to decreases in mitochondrial length and total mitochondrial mass in dendrites. Notably, BAX knockout mice also have fewer dendritic spines and less cellular Adenosine 5'triphosphate (ATP) in dendrites. The spine and ATP changes are abolished by restoring mitochondria fusion via overexpressing Mfn1 and Mfn2. These findings indicate that BAX-mediated mitochondrial fusion in neurons is crucial for the development of dendritic spines and the maintenance of cellular ATP levels.
    Keywords:  ATP; Mfn; mitochondria; spine
  3. Redox Biol. 2022 Jun 02. pii: S2213-2317(22)00129-X. [Epub ahead of print]54 102357
      Ischemic injury to the heart induces mitochondrial dysfunction due to increasing oxidative stress. MG53, also known as TRIM72, is highly expressed in striated muscle, is secreted as a myokine after exercise, and is essential for repairing damaged plasma membrane of many tissues by interacting with the membrane lipid phosphatidylserine (PS). We hypothesized MG53 could preserve mitochondrial integrity after an ischemic event by binding to the mitochondrial-specific lipid, cardiolipin (CL), for mitochondria protection to prevent mitophagy. Fluorescent imaging and Western blotting experiments showed recombinant human MG53 (rhMG53) translocated to the mitochondria after ischemic injury in vivo and in vitro. Fluorescent imaging indicated rhMG53 treatment reduced superoxide generation in ex vivo and in vitro models. Lipid-binding assay indicated MG53 binds to CL. Transfecting cardiomyocytes with the mitochondria-targeted mt-mKeima showed inhibition of mitophagy after MG53 treatment. Overall, we show that rhMG53 treatment may preserve cardiac function by preserving mitochondria in cardiomyocytes. These findings suggest MG53's interactions with mitochondria could be an attractive avenue for developing MG53 as a targeted protein therapy for cardioprotection.
    Keywords:  Cardiolipin; Cardioprotection; Cell membrane repair; Mitophagy; Myocardial infarction; TRIM72
  4. FEBS Lett. 2022 Jun 03.
      Mitochondria are involved in many cellular activities, including energy metabolism and biosynthesis of nucleotides, fatty acids, and amino acids. Mitochondrial morphology is a key factor in dictating mitochondrial functions. Here, we report that the acyl-CoA binding protein Acb1 in the fission yeast Schizosaccharomyces pombe is required for the maintenance of tubular mitochondrial morphology and proper mitochondrial respiration. The absence of Acb1 causes severe mitochondrial fragmentation in a dynamin-related protein Dnm1-dependent manner and impairs mitochondrial respiration. Moreover, Acb1 regulates the remodeling of lipid droplets in nutrient-rich conditions. Importantly, Acb1 promotes cell survival when cells are cultured in nutrient-rich medium. Hence, our findings establish roles of acyl-CoA binding proteins in regulating mitochondria, lipid droplets, and cell viability.
    Keywords:  Acyl-CoA-Binding Protein; Cell proliferation; Lipid droplets; Mitochondria; Schizosaccharomyces pombe
  5. J Mol Cell Cardiol. 2022 Jun 02. pii: S0022-2828(22)00100-6. [Epub ahead of print]170 22-33
      Angiotensin II (AngII) induces disruption of mitochondrial homeostasis and oxidative stress. Nuclear receptor NR4A1 (Nur77) plays an important role in vascular smooth muscle cells (VSMCs) function. However, the role of Nur77 in AngII-induced mitochondrial dynamics and oxidative stress in VSMCs remains unknown. In an in vitro model of AngII-treated cells, we discovered that Nur77 knockout aggravated AngII-induced oxidative stress in VSMCs, whereas activation of Nur77 by celastrol diminished them. Concomitantly, disturbance of mitochondrial dynamics induced by AngII was further exacerbated in Nur77 deficient VSMCs compared to wild-type (WT) VSMCs. Interestingly, Nur77 deletion increased mitochondrial fission but not fusion as evidenced by upregulated fission related genes (Fis1 and Drp1) but not fusion (Opa1 and Mfn2) under AngII stimulation in VSMCs. Mechanically, Nur77 could directly bind to the promoter regions of Fis1 and Drp1 and repress their transcription. Furthermore, we observed that Nur77 additionally promoted mitochondrial homeostasis by increasing mitophagic flux in a transcription-independent manner upon AngII challenge. By using an in vivo model of AngII-induced abdominal aortic aneurysm (AAA), we finally validated the protective role of Nur77 involved in the mitochondrial fission process and mitophagic flux in aortas, which was correlated with the occurrence and development of AAA in AngII-infused mice. Our data defines an essential role of Nur77 in regulating oxidative stress by maintaining mitochondrial homeostasis in VSMCs via both transcription-dependent and transcription-independent manner, supporting the therapeutic potential of Nur77 targeting in vascular diseases.
    Keywords:  Abdominal aortic aneurysm; Angiotensin II; Mitochondrial fission; Mitophagic flux; Nur77
  6. Shock. 2022 Jun 02.
      ABSTRACT: Resuscitation of trauma patients after haemorrhagic shock causes global ischemia/reperfusion (I/R) which may contribute to organ dysfunction. Oxidative stress resulting from I/R is known to induce signalling pathways leading to the production of inflammatory molecules culminating in organ dysfunction/injury. Our recent work demonstrated that oxidative stress was able to induce activation of the mitochondrial antiviral signaling protein (MAVS), a protein known to be involved in antiviral immunity, in an in vitro model. We therefore hypothesized that the MAVS pathway might be involved in I/R-induced inflammation and injury. The present studies show that MAVS is activated in vivo by liver I/R and in vitro in RAW 264.7 cells by hypoxia/reoxygenation (H/R). We utilized both in vivo (liver I/R in MAVS knockout mice) and in vitro (MAVS siRNA in RAW 264.7 cells followed by H/R) models to study the role of MAVS activation on downstream events. In vivo, we demonstrated augmented injury and inflammation in MAVS knockout mice compared to wild type animals, as shown by increasedhepatocellular injury, induction of hepatocyte apoptosis augmented plasma TNF-α levels. Further, in vitro silencing of MAVS by specific siRNA in RAW 264.7 and exposure of the cells to H/R caused activation of mitophagy. This may represent a compensatory response to increased liver inflammation. We conclude that activation of MAVS by hypoxia/reoxygenation dampens inflammation, potentially suggesting a novel target for intervention.
  7. Nature. 2022 Jun 08.
      Mitoribosomes are essential for the synthesis and maintenance of bioenergetic proteins. Here we use cryo-electron microscopy to determine a series of the small mitoribosomal subunit (SSU) intermediates in complex with auxiliary factors, revealing a sequential assembly mechanism. The methyltransferase TFB1M binds to partially unfolded rRNA h45 that is promoted by RBFA, while the mRNA channel is blocked. This enables binding of METTL15 that promotes further rRNA maturation and a large conformational change of RBFA. The new conformation allows initiation factor mtIF3 to already occupy the subunit interface during the assembly. Finally, the mitochondria-specific ribosomal protein mS37 (ref. 1) outcompetes RBFA to complete the assembly with the SSU-mS37-mtIF3 complex2 that proceeds towards mtIF2 binding and translation initiation. Our results explain how the action of step-specific factors modulate the dynamic assembly of the SSU, and adaptation of a unique protein, mS37, links the assembly to initiation to establish the catalytic human mitoribosome.