bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2023‒06‒25
seven papers selected by
Gavin McStay, Liverpool John Moores University
  1. PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems.
  2. Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function.
  3. DRP1-Mediated Mitophagy: Safeguarding Obese Hearts From Cardiomyopathy.
  4. Differential sensitivity of the yeast Lon protease Pim1p to impaired mitochondrial respiration.
  5. LonP1 Links Mitochondria-ER Interaction to Regulate Heart Function.
  6. Mitophagy suppresses motor neuron necroptotic mitochondrial damage and alleviates necroptosis that converges to SARM1 in acrylamide-induced dying-back neuropathy.
  7. Local GHR roles in regulation of mitochondrial function through mitochondrial biogenesis during myoblast differentiation.
  1. EMBO Rep. 2023 Jun 19. e56399
    PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems.
    Felix Kraus, Ellen A Goodall, Ian R Smith, Yizhi Jiang, Julia C Paoli, Frank Adolf, Jiuchun Zhang, Joao A Paulo, Brenda A Schulman, J Wade Harper.
      The protein kinase PINK1 and ubiquitin ligase Parkin promote removal of damaged mitochondria via a feed-forward mechanism involving ubiquitin (Ub) phosphorylation (pUb), Parkin activation, and ubiquitylation of mitochondrial outer membrane proteins to support the recruitment of mitophagy receptors. The ubiquitin ligase substrate receptor FBXO7/PARK15 is mutated in an early-onset parkinsonian-pyramidal syndrome. Previous studies have proposed a role for FBXO7 in promoting Parkin-dependent mitophagy. Here, we systematically examine the involvement of FBXO7 in depolarization and mt UPR-dependent mitophagy in the well-established HeLa and induced-neurons cell systems. We find that FBXO7-/- cells have no demonstrable defect in: (i) kinetics of pUb accumulation, (ii) pUb puncta on mitochondria by super-resolution imaging, (iii) recruitment of Parkin and autophagy machinery to damaged mitochondria, (iv) mitophagic flux, and (v) mitochondrial clearance as quantified by global proteomics. Moreover, global proteomics of neurogenesis in the absence of FBXO7 reveals no obvious alterations in mitochondria or other organelles. These results argue against a general role for FBXO7 in Parkin-dependent mitophagy and point to the need for additional studies to define how FBXO7 mutations promote parkinsonian-pyramidal syndrome.
    Keywords:  FBXO7; iNeurons; mitophagy; proteomics; ubiquitin ligase
    DOI:  https://doi.org/10.15252/embr.202256399
  2. Cell Mol Life Sci. 2023 Jun 20. 80(7): 183
    Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function.
    Lijun Chi, Dorothy Lee, Sharon Leung, Guanlan Hu, Bijun Wen, Paul Delgado-Olguin, Miluska Vissa, Ren Li, John H Brumell, Peter K Kim, Robert H J Bandsma.
      Peroxisomes are essential for mitochondrial health, as the absence of peroxisomes leads to altered mitochondria. However, it is unclear whether the changes in mitochondria are a function of preserving cellular function or a response to cellular damage caused by the absence of peroxisomes. To address this, we developed conditional hepatocyte-specific Pex16 deficient (Pex16 KO) mice that develop peroxisome loss and subjected them to a low-protein diet to induce metabolic stress. Loss of PEX16 in hepatocytes led to increased biogenesis of small mitochondria and reduced autophagy flux but with preserved capacity for respiration and ATP capacity. Metabolic stress induced by low protein feeding led to mitochondrial dysfunction in Pex16 KO mice and impaired biogenesis. Activation of PPARα partially corrected these mitochondrial disturbances, despite the absence of peroxisomes. The findings of this study demonstrate that the absence of peroxisomes in hepatocytes results in a concerted effort to preserve mitochondrial function, including increased mitochondrial biogenesis, altered morphology, and modified autophagy activity. Our study underscores the relationship between peroxisomes and mitochondria in regulating the hepatic metabolic responses to nutritional stressors.
    Keywords:  Fenofibrate; Malnutrition; Metabolism; Mitophagy; Nuclear hormone receptor; mTOR
    DOI:  https://doi.org/10.1007/s00018-023-04827-3
  3. Circ Res. 2023 Jun 23. 133(1): 22-24
    DRP1-Mediated Mitophagy: Safeguarding Obese Hearts From Cardiomyopathy.
    Xi Fang, Åsa B Gustafsson.
      
    Keywords:  Editorial; cardiovascular diseases; heart; mitochondria, mitophagy; obesity
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.323013
  4. J Biol Chem. 2023 Jun 16. pii: S0021-9258(23)01965-8. [Epub ahead of print] 104937
    Differential sensitivity of the yeast Lon protease Pim1p to impaired mitochondrial respiration.
    Meredith B Metzger, Jessica L Scales, Garis A Grant, Abigail E Molnar, Jadranka Loncarek, Allan M Weissman.
      Mitochondria are essential organelles whose proteome is well-protected by regulated protein degradation and quality control. While the ubiquitin-proteasome system can monitor mitochondrial proteins that reside at the mitochondrial outer membrane or are not successfully imported, resident proteases generally act on proteins within mitochondria. Herein, we assess the degradative pathways for mutant forms of three mitochondrial matrix proteins (mas1-1HA, mas2-11HA, and tim44-8HA) in Saccharomyces cerevisiae. The degradation of these proteins is strongly impaired by loss of either the m-AAA (Afg3p/Yta12p) or Lon (Pim1p) protease. We determine that these mutant proteins are all bona fide Pim1p substrates whose degradation is also blocked in respiratory-deficient "petite" yeast cells, such as in cells lacking m-AAA protease subunits. In contrast, matrix proteins that are substrates of the m-AAA protease are not affected by loss of respiration. The failure to efficiently remove Pim1p substrates in petite cells has no evident relationship to Pim1p maturation, localization, or assembly. However, Pim1p's auto-proteolysis is intact, and its overexpression restores substrate degradation, indicating that Pim1p retains some functionality in petite cells. Interestingly, chemical perturbation of mitochondria with oligomycin similarly prevents degradation of Pim1p substrates. Our results demonstrate that Pim1p activity is highly sensitive to mitochondrial perturbations such as loss of respiration or drug treatment in a manner that we do not observe with other proteases.
    Keywords:  ATP-dependent protease; Saccharomyces cerevisiae; mitochondria; mitochondria-associated degradation (MAD); protein turnover; quality control; respiration
    DOI:  https://doi.org/10.1016/j.jbc.2023.104937
  5. Research (Wash D C). 2023 ;6 0175
    LonP1 Links Mitochondria-ER Interaction to Regulate Heart Function.
    Yujie Li, Dawei Huang, Lianqun Jia, Fugen Shangguan, Shiwei Gong, Linhua Lan, Zhiyin Song, Juan Xu, Chaojun Yan, Tongke Chen, Yin Tan, Yongzhang Liu, Xingxu Huang, Carolyn K Suzuki, Zhongzhou Yang, Guanlin Yang, Bin Lu.
      Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and homeostasis. In particular, the mitochondria-endoplasmic reticulum (ER) membrane contact site (MAM) is known to regulate ion and lipid transfer, as well as signaling and organelle dynamics. However, the regulatory mechanisms of MAM formation and their function are still elusive. Here, we identify mitochondrial Lon protease (LonP1), a highly conserved mitochondrial matrix protease, as a new MAM tethering protein. The removal of LonP1 substantially reduces MAM formation and causes mitochondrial fragmentation. Furthermore, deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER (UPRER). Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart remodeling. These findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity, mitochondrial dynamics, and UPRER, offering exciting new insights into the potential therapeutic strategy for heart failure.
    DOI:  https://doi.org/10.34133/research.0175
  6. J Neurochem. 2023 Jun 23.
    Mitophagy suppresses motor neuron necroptotic mitochondrial damage and alleviates necroptosis that converges to SARM1 in acrylamide-induced dying-back neuropathy.
    Shuai Wang, Yiyu Yang, Zhigang Yu, Mingxue Song, Zhidan Liu, Shulin Shan, Hui Yong, Wenting Ni, Yalong Qiang, Cuiqin Zhang, Shu'e Wang, Xiulan Zhao, Fuyong Song.
      Acrylamide (ACR), a common industrial ingredient that is also found in many foodstuffs, induces dying-back neuropathy in humans and animals. However, the mechanisms remain poorly understood. Sterile alpha and toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is the central determinant of axonal degeneration and has crosstalk with different cell death programs to determine neuronal survival. Herein, we illustrated the role of SARM1 in ACR-induced dying-back neuropathy. We further demonstrated the upstream programmed cell death mechanism of this SARM1-dependent process. Spinal cord motor neurons that were induced to overexpress SARM1 underwent necroptosis rather than apoptosis in ACR neuropathy. Mechanically, non-canonical necroptotic pathways mediated mitochondrial permeability transition pore (mPTP) opening, reactive oxygen species (ROS) production, and mitochondrial fission. What's more, the final executioner of necroptosis, phosphorylation-activated mixed lineage kinase domain-like protein (MLKL), aggregated in mitochondrial fractions. Rapamycin intervention removed the impaired mitochondria, inhibited necroptosis for axon maintenance and neuronal survival, and alleviated ACR neuropathy. Our work clarified the functional links among mitophagy, necroptosis, and SARM1-dependent axonal destruction during ACR intoxication, providing novel therapeutic targets for dying-back neuropathies.
    Keywords:  SARM1; acrylamide; axonal necroptosis; dying-back neuropathy; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1111/jnc.15889
  7. Cell Commun Signal. 2023 06 19. 21(1): 148
    Local GHR roles in regulation of mitochondrial function through mitochondrial biogenesis during myoblast differentiation.
    Bowen Hu, Changbin Zhao, Xiangchun Pan, Haohui Wei, Guodong Mo, Mingjian Xian, Wen Luo, Qinghua Nie, Hongmei Li, Xiquan Zhang.
      BACKGROUND: Myoblast differentiation requires metabolic reprogramming driven by increased mitochondrial biogenesis and oxidative phosphorylation. The canonical GH-GHR-IGFs axis in liver exhibits a great complexity in response to somatic growth. However, the underlying mechanism of whether local GHR acts as a control valve to regulate mitochondrial function through mitochondrial biogenesis during myoblast differentiation remains unknown.METHODS: We manipulated the GHR expression in chicken primary myoblast to investigate its roles in mitochondrial biogenesis and function during myoblast differentiation.
    RESULTS: We reported that GHR is induced during myoblast differentiation. Local GHR promoted mitochondrial biogenesis during myoblast differentiation, as determined by the fluorescence intensity of Mito-Tracker Green staining and MitoTimer reporter system, the expression of mitochondrial biogenesis markers (PGC1α, NRF1, TFAM) and mtDNA encoded gene (ND1, CYTB, COX1, ATP6), as well as mtDNA content. Consistently, local GHR enhanced mitochondrial function during myoblast differentiation, as determined by the oxygen consumption rate, mitochondrial membrane potential, ATP level and ROS production. We next revealed that the regulation of mitochondrial biogenesis and function by GHR depends on IGF1. In terms of the underlying mechanism, we demonstrated that IGF1 regulates mitochondrial biogenesis via PI3K/AKT/CREB pathway. Additionally, GHR knockdown repressed myoblast differentiation.
    CONCLUSIONS: In conclusion, our data corroborate that local GHR acts as a control valve to enhance mitochondrial function by promoting mitochondrial biogenesis via IGF1-PI3K/AKT/CREB pathway during myoblast differentiation. Video Abstract.
    Keywords:  GHR; IGF1; Mitochondrial biogenesis; Mitochondrial function; Myoblast differentiation
    DOI:  https://doi.org/10.1186/s12964-023-01166-5
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