bims-mitpro 2024-03-24 papers

Issue of 2024–03–24
nine papers selected by
Andreas Kohler, Umeå University

Dev Cell. 2024 Mar 18. pii: S1534-5807(24)00110-2. [Epub ahead of print]

Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast.

Daiana N Moretti-Horten, Carlotta Peselj, Asli Aras Taskin, Lisa Myketin, Uwe Schulte, Oliver Einsle, Friedel Drepper, Marcin Luzarowski, F-Nora Vögtle.

Control of protein stoichiometry is essential for cell function. Mitochondrial oxidative phosphorylation (OXPHOS) presents a complex stoichiometric challenge as the ratio of the electron transport chain (ETC) and ATP synthase must be tightly controlled, and assembly requires coordinated integration of proteins encoded in the nuclear and mitochondrial genome. How correct OXPHOS stoichiometry is achieved is unknown. We identify the MitochondrialRegulatory hub for respiratoryAssembly (MiRA) platform, which synchronizes ETC and ATP synthase biogenesis in yeast. Molecularly, this is achieved by a stop-and-go mechanism: the uncharacterized protein Mra1 stalls complex IV assembly. Two "Go" signals are required for assembly progression: binding of the complex IV assembly factor Rcf2 and Mra1 interaction with an Atp9-translating mitoribosome induce Mra1 degradation, allowing synchronized maturation of complex IV and the ATP synthase. Failure of the stop-and-go mechanism results in cell death. MiRA controls OXPHOS assembly, ensuring correct stoichiometry of protein machineries encoded by two different genomes.

Keywords: complex stoichiometry; mitochondria; mitoribosome; protein complex assembly; protein import; protein quality control; respiratory chain

DOI: https://doi.org/10.1016/j.devcel.2024.02.011

Mol Cell. 2024 Mar 21. pii: S1097-2765(24)00168-0. [Epub ahead of print]84(6): 995-997

Integrating the response to stressed mitochondria.

Elliot Dine, Richard J Youle.

Chakrabarty et al.1 demonstrate that phospho-EIF2α (pEIF2α), the translation initiation factor that mediates the integrated stress response (ISR), is necessary and sufficient for the autophagic degradation of mitochondria following the addition of mitochondrial stressors.

DOI: https://doi.org/10.1016/j.molcel.2024.02.026

Mol Cell. 2024 Mar 21. pii: S1097-2765(24)00174-6. [Epub ahead of print]84(6): 1000-1002

A SIFI odyssey: Silencing the stress response amid mitochondrial import blockade to safeguard cell survival.

Yuleika G Martinez Castillo, Chantell S Evans.

In a recent study in Nature, Haakonsen et al.1 identify the SIFI complex as a stress response silencer via its E3 ligase activity to target unimported mitochondrial proteins and stress response components for degradation via the proteasome.

DOI: https://doi.org/10.1016/j.molcel.2024.02.034

J Cell Biol. 2024 May 06. pii: e202302069. [Epub ahead of print]223(5):

The phospholipids cardiolipin and phosphatidylethanolamine differentially regulate MDC biogenesis.

Tianyao Xiao, Alyssa M English, Zachary N Wilson, J Alan Maschek, James E Cox, Adam L Hughes.

Cells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.

DOI: https://doi.org/10.1083/jcb.202302069

J Integr Plant Biol. 2024 Mar 19.

A converged ubiquitin-proteasome pathway for the degradation of TOC and TOM tail-anchored receptors.

Meijing Yang, Shuai Chen, Shey-Li Lim, Lang Yang, Jia Yi Zhong, Koon Chuen Chan, Zhizhu Zhao, Kam-Bo Wong, Junqi Wang, Boon Leong Lim.

In plants, thousands of nucleus-encoded proteins translated in the cytosol are sorted to chloroplasts and mitochondria by binding to specific receptors of the TOC (translocon on the outer chloroplast membrane) and the TOM (translocon on the outer mitochondrial membrane) complexes for import into those organelles. The degradation pathways for these receptors are unclear. Here, we discovered a converged ubiquitin-proteasome pathway for the degradation of Arabidopsis thaliana TOC and TOM tail-anchored receptors. The receptors are ubiquitinated by E3 ligase(s) and pulled from the outer membranes by the AAA+ adenosine triphosphatase CDC48, after which a previously uncharacterized cytosolic protein, transmembrane domain (TMD)-binding protein for tail-anchored outer membrane proteins (TTOP), binds to the exposed TMDs at the C termini of the receptors and CDC48, and delivers these complexes to the 26S proteasome.

Keywords: 26S proteasome; CDC48; SP1; TOC; TOM; ubiquitination

DOI: https://doi.org/10.1111/jipb.13645

Eur J Cell Biol. 2024 Mar 15. pii: S0171-9335(24)00022-0. [Epub ahead of print]103(2): 151405

The small yeast GTPase Rho5 requires specific mitochondrial outer membrane proteins for translocation under oxidative stress and interacts with the VDAC Por1.

Linnet Bischof, Franziska Schweitzer, Hans-Peter Schmitz, Jürgen J Heinisch.

Yeast Rho5 is a small GTPase which mediates the response to nutrient and oxidative stress, and triggers mitophagy and apoptosis. We here studied the rapid translocation of a GFP-tagged Rho5 to mitochondria under such stress conditions by live-cell fluorescence microscopy in the background of strains lacking different mitochondrial outer membrane proteins (MOMP). Fun14, Msp1 and Alo1 were found to be required for efficient recruitment of the GTPase, whereas translocation of Dck1 and Lmo1, the subunits of its dimeric GDP/GTP exchange factor (GEF), remained unaffected. An influence of the voltage-dependent anion channel (VDAC) Por1 on the association of GFP-Rho5 with mitochondria under oxidative stress conditions appeared to be strain-dependent. However, epistasis analyses and bimolecular fluorescence complementation (BiFC) studies indicate a genetic and physical interaction. All four strains lacking a single MOMP were investigated for their effect on mitophagy.

Keywords: Rho-type GTPase; glucose starvation; mitochondria; oxidative stress; porin

DOI: https://doi.org/10.1016/j.ejcb.2024.151405

Apoptosis. 2024 Mar 17.

A novel mitochondrial unfolded protein response-related risk signature to predict prognosis, immunotherapy and sorafenib sensitivity in hepatocellular carcinoma.

Sidi Zhang, Hanyao Guo, Hongyu Wang, Xiaopeng Liu, Meixia Wang, Xiaoyu Liu, Yumei Fan, Ke Tan.

Hepatocellular carcinoma (HCC) is a common cause of cancer-associated death worldwide. The mitochondrial unfolded protein response (UPRmt) not only maintains mitochondrial integrity but also regulates cancer progression and drug resistance. However, no study has used the UPRmt to construct a prognostic signature for HCC. This work aimed to establish a novel signature for predicting patient prognosis, immune cell infiltration, immunotherapy, and chemotherapy response based on UPRmt-related genes (MRGs). Transcriptional profiles and clinical information were obtained from the TCGA and ICGC databases. Cox regression and LASSO regression analyses were applied to select prognostic genes and develop a risk model. The TIMER algorithm was used to investigate immunocytic infiltration in the high- and low-risk subgroups. Here, two distinct clusters were identified with different prognoses, immune cell infiltration statuses, drug sensitivities, and response to immunotherapy. A risk score consisting of seven MRGs (HSPD1, LONP1, SSBP1, MRPS5, YME1L1, HDAC1 and HDAC2) was developed to accurately and independently predict the prognosis of HCC patients. Additionally, the expression of core MRGs was confirmed by immunohistochemistry (IHC) staining, single-cell RNA sequencing, and spatial transcriptome analyses. Notably, the expression of prognostic MRGs was significantly correlated with sorafenib sensitivity in HCC and markedly downregulated in sorafenib-treated HepG2 and Huh7 cells. Furthermore, the knockdown of LONP1 decreased the proliferation, invasion, and migration of HepG2 cells, suggesting that upregulated LONP1 expression contributed to the malignant behaviors of HCC cells. To our knowledge, this is the first study to investigate the consensus clustering algorithm, prognostic potential, immune microenvironment infiltration and drug sensitivity based on the expression of MRGs in HCC. In summary, the UPRmt-related classification and prognostic signature could assist in determining the prognosis and personalized therapy of HCC patients from the perspectives of predictive, preventative and personalized medicine.

Keywords: Drug sensitivity; Hepatocellular carcinoma; Immune microenvironment; Mitochondrial unfolded protein response (UPRmt); Molecular subtypes

DOI: https://doi.org/10.1007/s10495-024-01945-6

Nat Metab. 2024 Mar 19.

Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons.

J Tabitha Hees, Simone Wanderoy, Jana Lindner, Marlena Helms, Hariharan Murali Mahadevan, Angelika B Harbauer.

Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 messenger RNA (mRNA) by tethering it to the mitochondrial surface. Here, we report that inhibition of AMP-activated protein kinase (AMPK) by activation of the insulin signalling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Notably, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin resistance in vitro by the key genetic Alzheimer risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity, especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signalling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s42255-024-01007-w