bims-mitpro 2024-05-26 papers

Issue of 2024‒05‒26
five papers selected by
Andreas Kohler, Umeå University

J Inherit Metab Dis. 2024 May 24.

Conserved quality control mechanisms of mitochondrial protein import.

Lion Borgert, Thomas Becker, Fabian den Brave.

Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co-factors and cellular signalling in apoptosis and inflammation. The functionality of mitochondria requires the import of about 900-1300 proteins from the cytosol in baker's yeast Saccharomyces cerevisiae and human cells, respectively. The vast majority of these proteins pass the outer membrane in a largely unfolded state through the translocase of the outer mitochondrial membrane (TOM) complex. Subsequently, specific protein translocases sort the precursor proteins into the outer and inner membranes, the intermembrane space and matrix. Premature folding of mitochondrial precursor proteins, defects in the mitochondrial protein translocases or a reduction of the membrane potential across the inner mitochondrial membrane can cause stalling of precursors at the protein import apparatus. Consequently, the translocon is clogged and non-imported precursor proteins accumulate in the cell, which in turn leads to proteotoxic stress and eventually cell death. To prevent such stress situations, quality control mechanisms remove non-imported precursor proteins from the TOM channel. The highly conserved ubiquitin-proteasome system of the cytosol plays a critical role in this process. Thus, the surveillance of protein import via the TOM complex involves the coordinated activity of mitochondria-localized and cytosolic proteins to prevent proteotoxic stress in the cell.

Keywords: TOM complex; mitoTAD; mitochondria; protein quality control; protein sorting

DOI: https://doi.org/10.1002/jimd.12756

Cell Stress Chaperones. 2024 May 17. pii: S1355-8145(24)00074-9. [Epub ahead of print]

Mitochondrial Chaperone Code: Just Warming Up.

R Felipe Perez, Gianna Mochi, Ariba Khan, Mark Woodford.

More than 99% of the mitochondrial proteome is encoded by the nucleus and requires refolding following import. Therefore, mitochondrial proteins require the coordinated action of molecular chaperones for their folding and activation. Several heat shock protein (Hsp) molecular chaperones, including members of the Hsp27, Hsp40/70, and Hsp90 families, as well as the chaperonin complex Hsp60/10 have an established role in mitochondrial protein import and folding. The 'Chaperone Code' describes the regulation of chaperone activity by dynamic post-translational modifications; however, little is known about post-translational regulation of mitochondrial chaperones. Dissecting the regulation of chaperone function is essential for understanding their differential regulation in pathogenic conditions and the potential development of efficacious therapeutic strategies. Here, we summarize the recent literature on post-translational regulation of mitochondrial chaperones, the consequences for mitochondrial function, and potential implications for disease.

Keywords: chaperones; heat shock proteins; metabolism; mitochondria; post-translational modification

DOI: https://doi.org/10.1016/j.cstres.2024.05.002

Cell Mol Life Sci. 2024 May 20. 81(1): 223

PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.

Lene Clausen, Justyna Okarmus, Vasileios Voutsinos, Morten Meyer, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen.

Parkinson's disease (PD) is a common and incurable neurodegenerative disorder that arises from the loss of dopaminergic neurons in the substantia nigra and is mainly characterized by progressive loss of motor function. Monogenic familial PD is associated with highly penetrant variants in specific genes, notably the PRKN gene, where homozygous or compound heterozygous loss-of-function variants predominate. PRKN encodes Parkin, an E3 ubiquitin-protein ligase important for protein ubiquitination and mitophagy of damaged mitochondria. Accordingly, Parkin plays a central role in mitochondrial quality control but is itself also subject to a strict protein quality control system that rapidly eliminates certain disease-linked Parkin variants. Here, we summarize the cellular and molecular functions of Parkin, highlighting the various mechanisms by which PRKN gene variants result in loss-of-function. We emphasize the importance of high-throughput assays and computational tools for the clinical classification of PRKN gene variants and how detailed insights into the pathogenic mechanisms of PRKN gene variants may impact the development of personalized therapeutics.

Keywords: AR-JP; DMS; MAVE; Mitochondria; PARK2; PRKN; Parkinson’s disease; Proteasome; Protein degradation; Protein folding; Protein quality control; Protein stability; Ubiquitin; VUS

DOI: https://doi.org/10.1007/s00018-024-05262-8

Biomolecules. 2024 May 18. pii: 598. [Epub ahead of print]14(5):

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation.

Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, José Manuel Romero Domínguez, Marta Talaverón-Rey, Diana Reche-López, Juan Miguel Suárez-Rivero, Mónica Álvarez-Córdoba, Ana Romero-González, Alejandra López-Cabrera, Marta Castro De Oliveira, Andrés Rodríguez-Sacristan, José Antonio Sánchez-Alcázar.

Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.

Keywords: EF-G1; GFM1; direct reprogramming; fibroblasts; induced neurons; mitochondria; mitochondrial diseases; mtUPR; treatment

DOI: https://doi.org/10.3390/biom14050598

Int J Mol Sci. 2024 May 16. pii: 5425. [Epub ahead of print]25(10):

Lon1 Inactivation Downregulates Autophagic Flux and Brassinosteroid Biogenesis, Modulating Mitochondrial Proportion and Seed Development in Arabidopsis.

Ce Song, Yuqi Hou, Tiantian Li, Yinyin Liu, Xian-Ao Wang, Wumei Qu, Lei Li.

Mitochondrial protein homeostasis is crucially regulated by protein degradation processes involving both mitochondrial proteases and cytosolic autophagy. However, it remains unclear how plant cells regulate autophagy in the scenario of lacking a major mitochondrial Lon1 protease. In this study, we observed a notable downregulation of core autophagy proteins in Arabidopsis Lon1 knockout mutant lon1-1 and lon1-2, supporting the alterations in the relative proportions of mitochondrial and vacuolar proteins over total proteins in the plant cells. To delve deeper into understanding the roles of the mitochondrial protease Lon1 and autophagy in maintaining mitochondrial protein homeostasis and plant development, we generated the lon1-2atg5-1 double mutant by incorporating the loss-of-function mutation of the autophagy core protein ATG5, known as atg5-1. The double mutant exhibited a blend of phenotypes, characterized by short plants and early senescence, mirroring those observed in the individual single mutants. Accordingly, distinct transcriptome alterations were evident in each of the single mutants, while the double mutant displayed a unique amalgamation of transcriptional responses. Heightened severity, particularly evident in reduced seed numbers and abnormal embryo development, was observed in the double mutant. Notably, aberrations in protein storage vacuoles (PSVs) and oil bodies were evident in the single and double mutants. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of genes concurrently downregulated in lon1-2, atg5-1, and lon1-2atg5-1 unveiled a significant suppression of genes associated with brassinosteroid (BR) biosynthesis and homeostasis. This downregulation likely contributes to the observed abnormalities in seed and embryo development in the mutants.

Keywords: Arabidopsis; Lon1; autophagy; brassinosteroid; mitochondrion

DOI: https://doi.org/10.3390/ijms25105425