bims-mitpro Biomed News
on Mitochondrial Proteostasis
Issue of 2023–12–31
six papers selected by
Andreas Kohler, Umeå University
  1. A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.
  2. Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH.
  3. PeFtsH5 negatively regulates the biological stress response in Phalaenopsis equestris mitochondria.
  4. Prohibitin 2: A key regulator of cell function.
  5. The role of lysine acetylation in the function of mitochondrial ribosomal protein L12.
  6. Powering down the mitochondrial LonP1 protease: a novel strategy for anticancer therapeutics.
  1. Mol Cell. 2023 Dec 21. pii: S1097-2765(23)01014-6. [Epub ahead of print]
    A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.
    Yuqiu Sun, Yu Cao, Huayun Wan, Adalet Memetimin, Yang Cao, Lin Li, Chongyang Wu, Meng Wang, She Chen, Qi Li, Yan Ma, Mengqiu Dong, Hui Jiang.
      Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.
    Keywords:  Cullin; FBXL4; PPTC7; metabolism; mitochondrial mass; mitophagy receptors BNIP3 and NIX; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.11.038
  2. Transl Stroke Res. 2023 Dec 26.
    Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH.
    Yang Liu, Chenbei Yao, Bin Sheng, Simin Zhi, Xiangxin Chen, Pengfei Ding, Jiatong Zhang, Zhennan Tao, Wei Li, Zong Zhuang, Jiannan Mao, Zheng Peng, Huiying Yan, Wei Jin.
      Subarachnoid hemorrhage (SAH) is a type of stroke with a high disability and mortality rate. Apoptosis caused by massive damage to mitochondria in neuron cells and inflammatory responses caused by high extracellular ATP lead to poor outcomes. USP30 is a deubiquitinating enzyme that inhibits mitophagy, resulting in a failure to remove damaged mitochondria in a timely manner after SAH; nevertheless, the pathway through which USP30 inhibits mitophagy is unknown. This study evaluated the neuroprotective role and possible molecular basis by which inhibiting USP30 to attenuate SAH-induced EBI by promoting neuronal mitophagy. We used an in vitro model of hemoglobin exposure and an in vivo model of intravascular perforation. Increased expression of USP30 was found after SAH in vivo and in vitro, and USP30 inhibition expression in SAH mice treated with MF094 resulted in significant improvement of neurological injury and inflammatory response and mediated good outcomes, suggesting a neuroprotective effect of USP30 inhibition. In cultured neurons, inhibition of USP30 promoted ubiquitination modification of mitochondrial fusion protein 2 (MFN2) by E3 ubiquitin ligase (Parkin), separating damaged mitochondria from the healthy mitochondrial network and prompting mitophagy, causing early clearance of damaged intracellular mitochondria, and reducing the onset of apoptosis. The high extracellular ATP environment was meliorated, reversing the conversion of microglia to a pro-inflammatory phenotype and reducing inflammatory injury. USP30 inhibition had no autophagy-promoting effect on structurally and functionally sound mitochondria and did not inhibit normal intracellular ATP production. The findings suggest that USP30 inhibition has a neuroprotective effect after SAH by promoting early mitophagy after SAH to clear damaged mitochondria.
    Keywords:  MF094; Mitochondrial fusion protein 2 (MFN2); Mitophagy; Subarachnoid hemorrhage (SAH); Ubiquitin-specific protease 30 (USP30); Ubiquitination
    DOI:  https://doi.org/10.1007/s12975-023-01228-3
  3. J Plant Physiol. 2023 Dec 12. pii: S0176-1617(23)00253-5. [Epub ahead of print]292 154159
    PeFtsH5 negatively regulates the biological stress response in Phalaenopsis equestris mitochondria.
    Yiding Wu, Yang Meng, Long Zhang, Zhenyu Yang, Mingyang Su, Ruidong Jia, Feng Ming.
      Mitochondrial homeostasis plays a crucial role in determining cell fate by direct influence on cell apoptosis and autophagy. The ATP and Zn2+-dependent protease FtsH are of paramount importance in maintaining mitochondrial homeostasis. In Phalaenopsis equestris, three mitochondrial FtsH proteases were identified, one of which was encoded by the PeFtsH5 gene. This gene encoded a distinctive mitochondrial protein featuring a unique domain within the FtsH family. Down-regulating the expression of the PeFtsH5 homolog in Nicotiana benthamiana resulted in elevated expression levels of SA synthesis-related genes, leading to enhanced disease resistance. However, this down-regulation also caused cellular damage. Similarly, in P. equestris, the down-regulation of PeFtsH5 expression promoted the expression of defense response genes, leading to accelerated apoptosis and increased ROS levels. Nonetheless, this down-regulation also positively influenced plant resistance to biotic stress. Notably, the PeFtsH5 (i-AAA) protein, as revealed by dual membrane experiments, could form homopolymers exclusively, as it did not interact with the other two mitochondrial FtsH proteases. Consequently, this mitochondrial FtsH protease functioned as a homopolymer within P. equestris cells. The findings of this study elucidated the role of PeFtsH5 in responding to biological stress and provided new insights into its potential molecular mechanism. The result presented in this study hold promise for future research endeavors examining the regulatory effects of mitochondrial proteases on mitochondrial homeostasis and the development of stress-resistant P. equestris varieties through breeding programs.
    Keywords:  Cell apoptosis; FtsH5; Mitochondria; Phalaenopsis equestris; Virus induced gene silencing (VIGS)
    DOI:  https://doi.org/10.1016/j.jplph.2023.154159
  4. Life Sci. 2023 Dec 22. pii: S0024-3205(23)01006-8. [Epub ahead of print] 122371
    Prohibitin 2: A key regulator of cell function.
    Bingjie Zhang, Wentao Li, Jiaying Cao, Yanhong Zhou, Xia Yuan.
      The PHB2 gene is located on chromosome 12p13 and encodes prohibitin 2, a highly conserved protein of 37 kDa. PHB2 is a dimer with antiparallel coils, possessing a unique negatively charged region crucial for its mitochondrial molecular chaperone functions. Thus, PHB2 plays a significant role in cell life activities such as mitosis, mitochondrial autophagy, signal transduction, and cell death. This review discusses how PHB2 inhibits transcription factors or nuclear receptors to maintain normal cell functions; how PHB2 in the cytoplasm or membrane ensures normal cell mitosis and regulates cell differentiation; how PHB2 affects mitochondrial structure, function, and cell apoptosis through mitochondrial intimal integrity and mitochondrial autophagy; how PHB2 affects mitochondrial stress and inhibits cell apoptosis by regulating cytochrome c migration and other pathways; how PHB2 affects cell growth, proliferation, and metastasis through a mitochondrial independent mechanism; and how PHB2 could be applied in disease treatment. We provide a theoretical basis and an innovative perspective for a comprehensive understanding of the role and mechanism of PHB2 in cell function regulation.
    Keywords:  Cell physiology; Drug targeting; Mitophagy; PHB2; Signal transduction
    DOI:  https://doi.org/10.1016/j.lfs.2023.122371
  5. Proteins. 2023 Dec 25.
    The role of lysine acetylation in the function of mitochondrial ribosomal protein L12.
    Katelynn V Paluch, Karlie R Platz, Emma J Rudisel, Ryan R Erdmann, Taylor R Laurin, Kristin E Dittenhafer-Reed.
      Mitochondria play a central role in energy production and cellular metabolism. Mitochondria contain their own small genome (mitochondrial DNA, mtDNA) that carries the genetic instructions for proteins required for ATP synthesis. The mitochondrial proteome, including the mitochondrial transcriptional machinery, is subject to post-translational modifications (PTMs), including acetylation and phosphorylation. We set out to determine whether PTMs of proteins associated with mtDNA may provide a potential mechanism for the regulation of mitochondrial gene expression. Here, we focus on mitochondrial ribosomal protein L12 (MRPL12), which is thought to stabilize mitochondrial RNA polymerase (POLRMT) and promote transcription. Numerous acetylation sites of MRPL12 were identified by mass spectrometry. We employed amino acid mimics of the acetylated (lysine to glutamine mutants) and deacetylated (lysine to arginine mutants) versions of MRPL12 to interrogate the role of lysine acetylation in transcription initiation in vitro and mitochondrial gene expression in HeLa cells. MRPL12 acetyl and deacetyl protein mimics were purified and assessed for their ability to impact mtDNA promoter binding of POLRMT. We analyzed mtDNA content and mitochondrial transcript levels in HeLa cells upon overexpression of acetyl and deacetyl mimics of MRPL12. Our results suggest that MRPL12 single-site acetyl mimics do not change the mtDNA promoter binding ability of POLRMT or mtDNA content in HeLa cells. Individual acetyl mimics may have modest effects on mitochondrial transcript levels. We found that the mitochondrial deacetylase, Sirtuin 3, is capable of deacetylating MRPL12 in vitro, suggesting a potential role for dynamic acetylation controlling MRPL12 function in a role outside of the regulation of gene expression.
    Keywords:  acetylation; mitochondrial DNA; mitochondrial genome; mitochondrial proteins; post-translational protein modification; transcription
    DOI:  https://doi.org/10.1002/prot.26654
  6. Expert Opin Ther Targets. 2023 Dec 29. 1-7
    Powering down the mitochondrial LonP1 protease: a novel strategy for anticancer therapeutics.
    Rahul Shetty, Roberto Noland, Ghata Nandi, Carolyn K Suzuki.
       INTRODUCTION: Mitochondrial LonP1 is an ATP-powered protease that also functions as an ATP-dependent chaperone. LonP1 plays a pivotal role in regulating mitochondrial proteostasis, metabolism and cell stress responses. Cancer cells exploit the functions of LonP1 to combat oncogenic stressors such as hypoxia, proteotoxicity, and oxidative stress, and to reprogram energy metabolism enabling cancer cell proliferation, chemoresistance, and metastasis.
    AREAS COVERED: LonP1 has emerged as a potential target for anti-cancer therapeutics. We review how cytoprotective functions of LonP1 can be leveraged by cancer cells to support oncogenic growth, proliferation, and survival. We also offer insights into small molecule inhibitors that target LonP1 by two distinct mechanisms: competitive inhibition of its protease activity and allosteric inhibition of its ATPase activity, both of which are crucial for its protease and chaperone functions.
    EXPERT OPINION: We highlight advantages of identifying specific, high-affinity allosteric inhibitors blocking the ATPase activity of LonP1. The future discovery of such inhibitors has potential application either alone or in conjunction with other anticancer agents, presenting an innovative approach and target for cancer therapeutics.
    Keywords:  AAA+ protease; ATP-powered protease; CDDO-Me; Cancer; Lon protease; LonP1; allosteric inhibitor; mitochondria
    DOI:  https://doi.org/10.1080/14728222.2023.2298358
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