bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022–01–23
seven papers selected by
Avinash N. Mukkala, University of Toronto
  1. Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
  2. Mitochondrial fusion, fission and mitophagy in cardiac diseases: challenges and therapeutic opportunities.
  3. Selective localization of Mfn2 near PINK1 enables its preferential ubiquitination by Parkin on mitochondria.
  4. FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury.
  5. Mitochondrial quality control in stroke: From the mechanisms to therapeutic potentials.
  6. Quantitative analysis of mitochondrial calcium uniporter (MCU) and essential MCU regulator (EMRE) in mitochondria from mouse tissues and HeLa cells.
  7. The isoquinoline PRL-295 increases the thermostability of Keap1 and disrupts its interaction with Nrf2.
  1. Neuron. 2022 Jan 13. pii: S0896-6273(21)01046-1. [Epub ahead of print]
    Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
    Juliet Goldsmith, Alban Ordureau, J Wade Harper, Erika L F Holzbaur.
      Neurons depend on autophagy to maintain cellular homeostasis, and defects in autophagy are pathological hallmarks of neurodegenerative disease. To probe the role of basal autophagy in the maintenance of neuronal health, we isolated autophagic vesicles from mouse brain tissue and used proteomics to identify the major cargos engulfed within autophagosomes, validating our findings in rodent primary and human iPSC-derived neurons. Mitochondrial proteins were identified as a major cargo in the absence of mitophagy adaptors such as OPTN. We found that nucleoid-associated proteins are enriched compared with other mitochondrial components. In the axon, autophagic engulfment of nucleoid-enriched mitochondrial fragments requires the mitochondrial fission machinery Drp1. We proposed that localized Drp1-dependent fission of nucleoid-enriched fragments in proximity to the sites of autophagosome biogenesis enhances their capture. The resulting efficient autophagic turnover of nucleoids may prevent accumulation of mitochondrial DNA in the neuron, thus mitigating activation of proinflammatory pathways that contribute to neurodegeneration.
    Keywords:  Drp1; TFAM; autophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis
    DOI:  https://doi.org/10.1016/j.neuron.2021.12.029
  2. 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
  3. Open Biol. 2022 Jan;12(1): 210255
    Selective localization of Mfn2 near PINK1 enables its preferential ubiquitination by Parkin on mitochondria.
    Marta Vranas, Yang Lu, Shafqat Rasool, Nathalie Croteau, Jonathan D Krett, Véronique Sauvé, Kalle Gehring, Edward A Fon, Thomas M Durcan, Jean-François Trempe.
      Mutations in Parkin and PINK1 cause early-onset familial Parkinson's disease. Parkin is a RING-In-Between-RING E3 ligase that transfers ubiquitin from an E2 enzyme to a substrate in two steps: (i) thioester intermediate formation on Parkin and (ii) acyl transfer to a substrate lysine. The process is triggered by PINK1, which phosphorylates ubiquitin on damaged mitochondria, which in turn recruits and activates Parkin. This leads to the ubiquitination of outer mitochondrial membrane proteins and clearance of the organelle. While the targets of Parkin on mitochondria are known, the factors determining substrate selectivity remain unclear. To investigate this, we examined how Parkin catalyses ubiquitin transfer to substrates. We found that His433 in the RING2 domain contributes to the catalysis of acyl transfer. In cells, the mutation of His433 impairs mitophagy. In vitro ubiquitination assays with isolated mitochondria show that Mfn2 is a kinetically preferred substrate. Using proximity-ligation assays, we show that Mfn2 specifically co-localizes with PINK1 and phospho-ubiquitin (pUb) in U2OS cells upon mitochondrial depolarization. We propose a model whereby ubiquitination of Mfn2 is efficient by virtue of its localization near PINK1, which leads to the recruitment and activation of Parkin via pUb at these sites.
    Keywords:  Mfn2; PINK1; Parkin; mitochondria; ubiquitin
    DOI:  https://doi.org/10.1098/rsob.210255
  4. Cell Signal. 2022 Jan 17. pii: S0898-6568(22)00009-2. [Epub ahead of print] 110249
    FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury.
    Haizhe Ji, Jin Wang, David Muid, Wei Song, Yinong Jiang, Hao Zhou.
      The mitochondrial unfolded protein response (UPRmt) is an adaptive transcriptional response involving the activation of proteases, chaperones, and antioxidant enzymes and serves to degrade abnormal or unfolded proteins and restore mitochondrial function. Although the cardioprotective action of the UPRmt has been verified in myocardial ischemia/reperfusion (I/R) injuries, the upstream signals involved remain unclear. Here, we explored the regulatory mechanisms underlying UPRmt in the reperfused mouse heart. UPRmt was slightly activated by I/R injury. UPRmt activation (using oligomycin) and inhibition (with the protease inhibitor AEBSF) respectively alleviated and augmented the reperfusion-mediated myocardial damage. Gene expression analysis demonstrated that oxidative stress was partly inhibited by UPRmt through upregulation of mitochondria-localized, not cytoplasmic, antioxidant enzymes. Contributing to cardiomyocyte survival under I/R, the transcription of pro-apoptotic proteins Bcl2 and c-IAP was also stimulated by UPRmt. Moreover, UPRmt upregulated mitochondrial fusion-related, but not fission-related, genes and stimulated the expression of mitochondrial biogenesis markers in reperfused hearts. Finally, we found that FUN14 domain containing 1 (FUNDC1)-mediated mitophagy induces the mitochondrial DNA decrease, triggering UPRmt. These results demonstrate that FUNDC1 functions upstream of the UPRmt to maintain mitochondrial quality control during myocardial I/R injury.
    Keywords:  Cardiomyocyte; FUNDC1; Mitochondrial unfolded protein response; Mitophagy; Myocardial I/R injury
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110249
  5. J Cell Mol Med. 2022 Jan 17.
    Mitochondrial quality control in stroke: From the mechanisms to therapeutic potentials.
    Heyan Tian, Xiangyu Chen, Jun Liao, Tong Yang, Shaowu Cheng, Zhigang Mei, Jinwen Ge.
      Mitochondrial damage is a critical contributor to stroke-induced injury, and mitochondrial quality control (MQC) is the cornerstone of restoring mitochondrial homeostasis and plays an indispensable role in alleviating pathological process of stroke. Mitochondria quality control promotes neuronal survival via various adaptive responses for preserving mitochondria structure, morphology, quantity and function. The processes of mitochondrial fission and fusion allow for damaged mitochondria to be segregated and facilitate the equilibration of mitochondrial components such as DNA, proteins and metabolites. The process of mitophagy is responsible for the degradation and recycling of damaged mitochondria. This review aims to offer a synopsis of the molecular mechanisms involved in MQC for recapitulating our current understanding of the complex role that MQC plays in the progression of stroke. Speculating on the prospect that targeted manipulation of MQC mechanisms may be exploited for the rationale design of novel therapeutic interventions in the ischaemic stroke and haemorrhagic stroke. In the review, we highlight the potential of MQC as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy; stroke
    DOI:  https://doi.org/10.1111/jcmm.17189
  6. FEBS Open Bio. 2022 Jan 21.
    Quantitative analysis of mitochondrial calcium uniporter (MCU) and essential MCU regulator (EMRE) in mitochondria from mouse tissues and HeLa cells.
    Akira Watanabe, Kousuke Maeda, Atsushi Nara, Mei Hashida, Mizune Ozono, Ayaka Nakao, Akiko Yamada, Yasuo Shinohara, Takenori Yamamoto.
      Mitochondrial calcium homeostasis plays critical roles in cell survival and aerobic metabolism in eukaryotes. The calcium uniporter is a highly selective calcium ion channel consisting of several subunits. Mitochondrial calcium uniporter (MCU) and essential MCU regulator (EMRE) are core subunits of the calcium uniporter required for calcium uptake activity in the mitochondria. Recent 3D structure analysis of the MCU-EMRE complex reconstituted in nanodiscs revealed that the human MCU exists as a tetramer forming a channel pore, with EMRE bound to each MCU at a 1:1 ratio. However, the stoichiometry of MCU and EMRE in the mitochondria has not yet been investigated. We here quantitatively examined the protein levels of MCU and EMRE in the mitochondria from mouse tissues by using characterized antibodies and standard proteins. Unexpectedly, the number of EMRE molecules was lower than that of MCU; moreover, the ratios between MCU and EMRE were significantly different among tissues. Statistical calculations based on our findings suggest that a MCU tetramer binding to 4 EMREs may exist, but at low levels in the mitochondrial inner membrane. In brain mitochondria, the majority of MCU tetramers bind to 2 EMREs; in mitochondria in liver, kidney, and heart, MCU tetramers bind to 1 EMRE; and in kidney and heart, almost half of MCU tetramers bound to no EMRE. We propose here a novel stoichiometric model of the MCU-EMRE complex in mitochondria.
    Keywords:  Calcium uniporter; EMRE; Ion channel; MCU; Mitochondria; stoichiometry
    DOI:  https://doi.org/10.1002/2211-5463.13371
  7. iScience. 2022 Jan 21. 25(1): 103703
    The isoquinoline PRL-295 increases the thermostability of Keap1 and disrupts its interaction with Nrf2.
    Sharadha Dayalan Naidu, Takafumi Suzuki, Dina Dikovskaya, Elena V Knatko, Maureen Higgins, Miu Sato, Miroslav Novak, José A Villegas, Terry W Moore, Masayuki Yamamoto, Albena T Dinkova-Kostova.
      Transcription factor Nrf2 and its negative regulator Keap1 orchestrate a cytoprotective response against oxidative, metabolic, and inflammatory stress. Keap1 is a drug target, with several small molecules in drug development. Here, we show that the isoquinoline PRL-295 increased Keap1 thermostability in lysates from cells expressing fluorescently tagged Keap1. The thermostability of endogenous Keap1 also increased in intact cells and murine liver following PRL-295 treatment. Fluorescence Lifetime Imaging-Förster Resonance Energy Transfer (FLIM-FRET) experiments in cells co-expressing sfGFP-Nrf2 and Keap1-mCherry further showed that PRL-295 prolonged the donor fluorescence lifetime, indicating disruption of the Keap1-Nrf2 protein complex. Orally administered PRL-295 to mice activated the Nrf2transcriptional target NAD(P)H:quinone oxidoreductase 1 (NQO1) in liver and decreased the levels of plasma alanine aminotransferase and aspartate aminotransferase upon acetaminophen-induced hepatic injury. Thus, PRL-295 engages the Keap1 protein target in cells and in vivo, disrupting its interaction with Nrf2, leading to activation of Nrf2-dependent transcription and hepatocellular protection.
    Keywords:  Biochemistry; Biological sciences; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2021.103703
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