bims-mitpro 2024-12-01 papers

Issue of 2024–12–01
five papers selected by
Andreas Kohler, Umeå University

Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2410486121

ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.

Hyunbae Kim, Qi Chen, Donghong Ju, Neeraja Purandare, Xuequn Chen, Lobelia Samavati, Li Li, Ren Zhang, Lawrence I Grossman, Kezhong Zhang.

The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.

Keywords: ER-mitochondria contact; cell metabolism; michondrial UPR; transcriptional regulation; unfolded protein response

DOI: https://doi.org/10.1073/pnas.2410486121

Int J Biochem Cell Biol. 2024 Nov 26. pii: S1357-2725(24)00197-3. [Epub ahead of print] 106704

Unveiling a novel signalling pathway involving NRF2 and PGAM5 in regulating the mitochondrial unfolded protein response in stressed cardiomyocytes.

Rahme Nese Safakli, Stephen Gray, Nadia Bernardi, Ioannis Smyrnias.

The mitochondrial unfolded protein response (UPRmt) is a conserved signalling pathway that initiates a specific transcriptional programme to maintain mitochondrial and cellular homeostasis under stress. Previous studies have demonstrated that UPRmt activation has protective effects in the pressure-overloaded human heart, suggesting that robust UPRmt stimulation could serve as an intervention strategy for cardiovascular diseases. However, the precise mechanisms of UPRmt regulation remain unclear. In this study, we present evidence that the NRF2 transcription factor is involved in UPRmt activation in cardiomyocytes during conditions of mitochondrial stress. Silencing NRF2 partially reduces UPRmt activation, highlighting its essential role in this pathway. However, constitutive activation of NRF2 via inhibition of its cytosolic regulator KEAP1 does not increase levels of UPRmt activation markers, suggesting an alternative regulatory mechanism independent of the canonical KEAP1-NRF2 axis. Further analysis revealed that NRF2 likely affects UPRmt activation through its interaction with PGAM5 at the mitochondrial membrane. Disruption of PGAM5 in cardiomyocytes subjected to mitochondrial stress reduces the interaction between PGAM5 and NRF2, enhancing nuclear translocation of NRF2 and significantly upregulating the UPRmt in an NRF2-dependent manner. This NRF2-regulated UPRmt amplification improves mitochondrial respiration, reflecting an enhanced capacity for cardiomyocytes to meet elevated energetic demands during mitochondrial stress. Our findings highlight the therapeutic potential of targeting the NRF2-PGAM5-KEAP1 signalling complex to amplify the UPRmt in cardiomyocytes for cardiovascular and other diseases associated with mitochondrial dysfunction. Future studies should aim to elucidate the mechanisms via which NRF2 enhances the protective effects of UPRmt, thereby contributing to more targeted therapeutic approaches.

Keywords: cardiomyocytes; cardioprotection; mitochondria; stress; unfolded protein response

DOI: https://doi.org/10.1016/j.biocel.2024.106704

Ageing Res Rev. 2024 Nov 26. pii: S1568-1637(24)00421-5. [Epub ahead of print] 102603

The Mitochondrial Integrated Stress Response: A novel approach to anti-aging and pro-longevity.

Xiaoding Wang, Guangyu Zhang.

The ISR is a cellular signaling pathway that responds to various physiological changes and types of stimulation. The mitochondrial integrated stress response (ISRmt) is a stress response specific to mitochondria which is initiated by eIF2α phosphorylation and is responsive to mitochondrial stressors. The ISRmt triggers diverse metabolic responses reliant on activating transcription factor 4 (ATF4). The preliminary phases of ISRmt can provoke an adaptive stress response that antagonizes age-related diseases and promotes longevity. In this review, we provide an overview of the molecular mechanisms of the ISRmt, with a particular focus on its potential as a therapeutic target for age-related disease and the promotion of longevity.

Keywords: FGF21; Mitochondrial integrated stress response; aging; longevity

DOI: https://doi.org/10.1016/j.arr.2024.102603

bioRxiv. 2024 Nov 13. pii: 2024.11.12.623337. [Epub ahead of print]

Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.

Wenqian Chen, Jie Yang, Gabriel C Lander.

The human ClpXP complex (hClpXP) plays a central role in mitochondrial protein quality control by degrading misfolded or unneeded proteins. While bacterial ClpXP complexes have been extensively characterized, the molecular determinants underlying hClpXP assembly and regulation are not as well understood. We determined cryo-electron microscopy (cryo-EM) structures of hClpP in isolation and in complex with hClpX, revealing how hClpX binding promotes rearrangement of an asymmetric hClpP heptamer to assemble as a symmetric tetradecamer. Our hClpXP structure also highlights the stabilizing role of a previously uncharacterized eukaryotic ClpX sequence, referred to as the E-loop, and its importance in ATPase activity and hexamer assembly. We further show that peptide interaction with the hClpP proteolytic active site promotes the complex to adopt a proteolytically competent conformation. Together, these findings advance our understanding of the molecular mechanisms defining hClpXP activation and function.

DOI: https://doi.org/10.1101/2024.11.12.623337

Structure. 2024 Nov 19. pii: S0969-2126(24)00487-8. [Epub ahead of print]

Protein translocation through α-helical channels and insertases.

Jingxia Chen, Xueyin Zhou, Yuqi Yang, Long Li.

Protein translocation systems are essential for distributing proteins across various lipid membranes in cells. Cellular membranes, such as the endoplasmic reticulum (ER) membrane and mitochondrial inner membrane, require highly regulated protein translocation machineries that specifically allow the passage of protein polypeptides while blocking smaller molecules like ions and water. Key translocation systems include the Sec translocation channel, the protein insertases of the Oxa1 superfamily, and the translocases of the mitochondrial inner membrane (TIM). These machineries utilize different mechanisms to create pathways for proteins to move across membranes while preventing ion leakage during the dynamic translocation processes. In this review, we highlight recent advances in our understanding of these α-helical translocation machineries and examine their structures, mechanisms, and regulation. We also discuss the therapeutic potential of these translocation pathways and summarize the progress in drug development targeting these systems for treating diseases.

DOI: https://doi.org/10.1016/j.str.2024.10.032