bims-mitpro 2024-06-16 papers

bims-mitpro

Biomed News

on Mitochondrial Proteostasis

Issue of 2024‒06‒16
eight papers selected by
Andreas Kohler, Umeå University

Reproductive regulation of the mitochondrial stress response in Caenorhabditis elegans.
Privileged proteins with a second residence: dual targeting and conditional re-routing of mitochondrial proteins.
Role of Yme1 in mitochondrial protein homeostasis: from regulation of protein import, OXPHOS function to lipid synthesis and mitochondrial dynamics.
Unique architectural features of mammalian mitochondrial protein synthesis.
The Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy.
Mitochondrial quality control dysfunction in osteoarthritis: Mechanisms, therapeutic strategies & future prospects.
Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.
MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.

Cell Rep. 2024 Jun 07. pii: S2211-1247(24)00664-8. [Epub ahead of print]43(6): 114336

Reproductive regulation of the mitochondrial stress response in Caenorhabditis elegans.

Nikolaos Charmpilas, Aggeliki Sotiriou, Konstantinos Axarlis, Nektarios Tavernarakis, Thorsten Hoppe.

  Proteome integrity is fundamental for cellular and organismal homeostasis. The mitochondrial unfolded protein response (UPRmt), a key component of the proteostasis network, is activated in a non-cell-autonomous manner in response to mitochondrial stress in distal tissues. However, the importance of inter-tissue communication for UPRmt inducibility under physiological conditions remains elusive. Here, we show that an intact germline is essential for robust UPRmt induction in the Caenorhabditis elegans somatic tissues. A series of nematode mutants with germline defects are unable to respond to genetic or chemical UPRmt inducers. Our genetic analysis suggests that reproductive signals, rather than germline stem cells, are responsible for somatic UPRmt induction. Consistent with this observation, we show that UPRmt is sexually dimorphic, as male nematodes are inherently unresponsive to mitochondrial stress. Our findings highlight a paradigm of germline-somatic communication and suggest that reproductive cessation is a primary cause of age-related UPRmt decline.

Keywords:  C. elegans; CP: Developmental biology; CP: Molecular biology; aging; germline; mitochondria; proteostasis; unfolded protein response

DOI:  https://doi.org/10.1016/j.celrep.2024.114336
FEBS J. 2024 Jun 10.

Privileged proteins with a second residence: dual targeting and conditional re-routing of mitochondrial proteins.

Ophry Pines, Margalit Horwitz, Johannes M Herrmann.

  Almost all mitochondrial proteins are encoded by nuclear genes and synthesized in the cytosol as precursor proteins. Signals in the amino acid sequence of these precursors ensure their targeting and translocation into mitochondria. However, in many cases, only a certain fraction of a specific protein is transported into mitochondria, while the rest either remains in the cytosol or undergoes reverse translocation to the cytosol, and can populate other cellular compartments. This phenomenon is called dual localization which can be instigated by different mechanisms. These include alternative start or stop codons, differential transcripts, and ambiguous or competing targeting sequences. In many cases, dual localization might serve as an economic strategy to reduce the number of required genes; for example, when the same groups of enzymes are required both in mitochondria and chloroplasts or both in mitochondria and the nucleus/cytoplasm. Such cases frequently employ ambiguous targeting sequences to distribute proteins between both organelles. However, alternative localizations can also be used for signaling, for example when non-imported precursors serve as mitophagy signals or when they represent transcription factors in the nucleus to induce the mitochondrial unfolded stress response. This review provides an overview regarding the mechanisms and the physiological consequences of dual targeting.

Keywords:  dual targeting; mitochondria; protein import; start codon; targeting signals

DOI:  https://doi.org/10.1111/febs.17191
Biochem Soc Trans. 2024 Jun 12. pii: BST20240450. [Epub ahead of print]

Role of Yme1 in mitochondrial protein homeostasis: from regulation of protein import, OXPHOS function to lipid synthesis and mitochondrial dynamics.

Kwan Ting Kan, Joel Wilcock, Hui Lu.

  Mitochondria are essential organelles of eukaryotic cells and thus mitochondrial proteome is under constant quality control and remodelling. Yme1 is a multi-functional protein and subunit of the homo-hexametric complex i-AAA proteinase. Yme1 plays vital roles in the regulation of mitochondrial protein homeostasis and mitochondrial plasticity, ranging from substrate degradation to the regulation of protein functions involved in mitochondrial protein biosynthesis, energy production, mitochondrial dynamics, and lipid biosynthesis and signalling. In this mini review, we focus on discussing the current understanding of the roles of Yme1 in mitochondrial protein import via TIM22 and TIM23 pathways, oxidative phosphorylation complex function, as well as mitochondrial lipid biosynthesis and signalling, as well as a brief discussion of the role of Yme1 in modulating mitochondrial dynamics.

Keywords:  i-AAA proteinase; mitochondrial protein homeostasis; mitochondrial protein import; oxidative phosphorylation complex; protein function

DOI:  https://doi.org/10.1042/BST20240450
Trends Cell Biol. 2024 Jun 08. pii: S0962-8924(24)00097-7. [Epub ahead of print]

Unique architectural features of mammalian mitochondrial protein synthesis.

Oliver Rackham, Martin Saurer, Nenad Ban, Aleksandra Filipovska.

  Mitochondria rely on coordinated expression of their own mitochondrial DNA (mtDNA) with that of the nuclear genome for their biogenesis. The bacterial ancestry of mitochondria has given rise to unique and idiosyncratic features of the mtDNA and its expression machinery that can be specific to different organisms. In animals, the mitochondrial protein synthesis machinery has acquired many new components and mechanisms over evolution. These include several new ribosomal proteins, new stop codons and ways to recognise them, and new mechanisms to deliver nascent proteins into the mitochondrial inner membrane. Here we describe the mitochondrial protein synthesis machinery in mammals and its unique mechanisms of action elucidated to date and highlight the technologies poised to reveal the next generation of discoveries in mitochondrial translation.

Keywords:  RNA; mitochondria; mitochondrial disease; ribosomes; translation

DOI:  https://doi.org/10.1016/j.tcb.2024.05.001
Circ Res. 2024 Jun 14.

The Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy.

Wenjuan Wang, Ermin Li, Jianqiu Zou, Chen Qu, Juan Ayala, Yuan Wen, Md Sadikul Islam, Neal L Weintraub, David J Fulton, Qiangrong Liang, Jiliang Zhou, Jinbao Liu, Jie Li, Yi Sun, Huabo Su.

  BACKGROUND: Clearance of damaged mitochondria via mitophagy is crucial for cellular homeostasis. Apart from Parkin, little is known about additional Ub (ubiquitin) ligases that mediate mitochondrial ubiquitination and turnover, particularly in highly metabolically active organs such as the heart.METHODS: In this study, we have combined in silico analysis and biochemical assay to identify CRL (cullin-RING ligase) 5 as a mitochondrial Ub ligase. We generated cardiomyocytes and mice lacking RBX2 (RING-box protein 2; also known as SAG [sensitive to apoptosis gene]), a catalytic subunit of CRL5, to understand the effects of RBX2 depletion on mitochondrial ubiquitination, mitophagy, and cardiac function. We also performed proteomics analysis and RNA-sequencing analysis to define the impact of loss of RBX2 on the proteome and transcriptome.
RESULTS: RBX2 and CUL (cullin) 5, 2 core components of CRL5, localize to mitochondria. Depletion of RBX2 inhibited mitochondrial ubiquitination and turnover, impaired mitochondrial membrane potential and respiration, increased cardiomyocyte cell death, and has a global impact on the mitochondrial proteome. In vivo, deletion of the Rbx2 gene in adult mouse hearts suppressed mitophagic activity, provoked accumulation of damaged mitochondria in the myocardium, and disrupted myocardial metabolism, leading to the rapid development of dilated cardiomyopathy and heart failure. Similarly, ablation of RBX2 in the developing heart resulted in dilated cardiomyopathy and heart failure. The action of RBX2 in mitochondria is not dependent on Parkin, and Parkin gene deletion had no impact on the onset and progression of cardiomyopathy in RBX2-deficient hearts. Furthermore, RBX2 controls the stability of PINK1 in mitochondria.
CONCLUSIONS: These findings identify RBX2-CRL5 as a mitochondrial Ub ligase that regulates mitophagy and cardiac homeostasis in a Parkin-independent, PINK1-dependent manner.

Keywords:  heart failure; mitochondria; mitophagy; protein kinases; ubiquitination

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324285
Arch Gerontol Geriatr. 2024 Jun 04. pii: S0167-4943(24)00198-5. [Epub ahead of print]125 105522

Mitochondrial quality control dysfunction in osteoarthritis: Mechanisms, therapeutic strategies & future prospects.

Chiyuen Cheung, Shaoqin Tu, Yi Feng, Chuiming Wan, Hong Ai, Zheng Chen.

  Osteoarthritis (OA) is a prevalent chronic joint disease characterized by articular cartilage degeneration, pain, and disability. Emerging evidence indicates that mitochondrial quality control dysfunction contributes to OA pathogenesis. Mitochondria are essential organelles to generate cellular energy via oxidative phosphorylation and regulate vital processes. Impaired mitochondria can negatively impact cellular metabolism and result in the generation of harmful reactive oxygen species (ROS). Dysfunction in mitochondrial quality control mechanisms has been increasingly linked to OA onset and progression. This review summarizes current knowledge on the role of mitochondrial quality control disruption in OA, highlighting disturbed mitochondrial dynamics, impaired mitochondrial biogenesis, antioxidant defenses and mitophagy. The review also discusses potential therapeutic strategies targeting mitochondrial Quality Control in OA, offering future perspectives on advancing OA therapeutic strategies.

Keywords:  Mitochondrial dysfunction; Mitochondrial quality control; Mitophagy; Osteoarthritis; Oxidative stress

DOI:  https://doi.org/10.1016/j.archger.2024.105522
Cell Mol Life Sci. 2024 Jun 10. 81(1): 254

Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.

Yingzhen Du, Jialei Li, Zhe Dai, Yuxin Chen, Yao Zhao, Xiaoman Liu, Tian Xia, Pingjun Zhu, Yijin Wang.

  The endogenous mitochondrial quality control (MQC) system serves to protect mitochondria against cellular stressors. Although mitochondrial dysfunction contributes to cardiac damage during many pathological conditions, the regulatory signals influencing MQC disruption during septic cardiomyopathy (SC) remain unclear. This study aimed to investigate the involvement of pyruvate kinase M2 (PKM2) and prohibitin 2 (PHB2) interaction followed by MQC impairment in the pathogenesis of SC. We utilized LPS-induced SC models in PKM2 transgenic (PKM2TG) mice, PHB2S91D-knockin mice, and PKM2-overexpressing HL-1 cardiomyocytes. After LPS-induced SC, cardiac PKM2 expression was significantly downregulated in wild-type mice, whereas PKM2 overexpression in vivo sustained heart function, suppressed myocardial inflammation, and attenuated cardiomyocyte death. PKM2 overexpression relieved sepsis-related mitochondrial damage via MQC normalization, evidenced by balanced mitochondrial fission/fusion, activated mitophagy, restored mitochondrial biogenesis, and inhibited mitochondrial unfolded protein response. Docking simulations, co-IP, and domain deletion mutant protein transfection experiments showed that PKM2 phosphorylates PHB2 at Ser91, preventing LPS-mediated PHB2 degradation. Additionally, the A domain of PKM2 and the PHB domain of PHB2 are required for PKM2-PHB2 binding and PHB2 phosphorylation. After LPS exposure, expression of a phosphorylation-defective PHB2S91A mutant negated the protective effects of PKM2 overexpression. Moreover, knockin mice expressing a phosphorylation-mimetic PHB2S91D mutant showed improved heart function, reduced inflammation, and preserved mitochondrial function following sepsis induction. Abundant PKM2 expression is a prerequisite to sustain PKM2-PHB2 interaction which is a key element for preservation of PHB2 phosphorylation and MQC, presenting novel interventive targets for the treatment of septic cardiomyopathy.

Keywords:  MQC; Mitochondria; PHB2; PKM2; Septic cardiomyopathy

DOI:  https://doi.org/10.1007/s00018-024-05253-9
Cell. 2024 Jun 05. pii: S0092-8674(24)00526-9. [Epub ahead of print]

MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.

Luis Carlos Tábara, Stephen P Burr, Michele Frison, Suvagata R Chowdhury, Vincent Paupe, Yu Nie, Mark Johnson, Jara Villar-Azpillaga, Filipa Viegas, Mayuko Segawa, Hanish Anand, Kasparas Petkevicius, Patrick F Chinnery, Julien Prudent.

  Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.

Keywords:  IMM quality control; IMM remodeling; MTFP1; autophagy; fission and fusion; mitochondria; mitochondrial dynamics; mitophagy; mtDNA

DOI:  https://doi.org/10.1016/j.cell.2024.05.017