bims-mitpro 2023-11-26 papers

Issue of 2023–11–26
four papers selected by
Andreas Kohler, Umeå University

Nat Commun. 2023 Nov 22. 14(1): 7636

The heat shock protein LarA activates the Lon protease in response to proteotoxic stress.

Deike J Omnus, Matthias J Fink, Aswathy Kallazhi, Maria Xandri Zaragoza, Axel Leppert, Michael Landreh, Kristina Jonas.

The Lon protease is a highly conserved protein degradation machine that has critical regulatory and protein quality control functions in cells from the three domains of life. Here, we report the discovery of a α-proteobacterial heat shock protein, LarA, that functions as a dedicated Lon regulator. We show that LarA accumulates at the onset of proteotoxic stress and allosterically activates Lon-catalysed degradation of a large group of substrates through a five amino acid sequence at its C-terminus. Further, we find that high levels of LarA cause growth inhibition in a Lon-dependent manner and that Lon-mediated degradation of LarA itself ensures low LarA levels in the absence of stress. We suggest that the temporal LarA-dependent activation of Lon helps to meet an increased proteolysis demand in response to protein unfolding stress. Our study defines a regulatory interaction of a conserved protease with a heat shock protein, serving as a paradigm of how protease activity can be tuned under changing environmental conditions.

DOI: https://doi.org/10.1038/s41467-023-43385-x

Biochem Soc Trans. 2023 Nov 21. pii: BST20230377. [Epub ahead of print]

Mechanisms of stress management in mitochondrial protein import.

Maryam Mukhtar, Krutika Thakkur, Agnieszka Chacinska, Piotr Bragoszewski.

Mitochondria are vital to the functions of eukaryotic cells. Most mitochondrial proteins are transported into the organelle following their synthesis by cytoplasmic ribosomes. However, precise protein targeting is complex because the two diverse lipid membranes encase mitochondria. Efficient protein translocation across membranes and accurate sorting to specific sub-compartments require the cooperation of multiple factors. Any failure in mitochondrial protein import can disrupt organelle fitness. Proteins intended for mitochondria make up a significant portion of all proteins produced in the cytosol. Therefore, import defects causing their mislocalization can significantly stress cellular protein homeostasis. Recognition of this phenomenon has increased interest in molecular mechanisms that respond to import-related stress and restore proteostasis, which is the focus of this review. Significantly, disruptions in protein homeostasis link strongly to the pathology of several degenerative disorders highly relevant in ageing societies. A comprehensive understanding of protein import quality control will allow harnessing this machinery in therapeutic approaches.

Keywords: mitochondria; protein degradation; protein transport; proteostasis; proteotoxicity; stress

DOI: https://doi.org/10.1042/BST20230377

Poult Sci. 2023 Oct 28. pii: S0032-5791(23)00766-6. [Epub ahead of print]103(1): 103247

Drp1 regulated PINK1-dependent mitophagy protected duck follicular granulosa cells from acute heat stress injury.

Chen Yang, Pei Luo, You-Tian Yang, Xin-Liang Fu, Bing-Xin Li, Xu Shen, Dan-Ning Xu, Yun-Mao Huang, Yun-Bo Tian, Wen-Jun Liu.

The mitochondrial quality control system is crucial in maintaining cellular homeostasis during environmental stress. Granulosa cells are the main cells secreting steroid hormones, and mitochondria are the key organelles for steroid hormone synthesis. The impact of the mitochondrial quality control system on granulosa cells' steroid hormone synthesis and survival under heat stress is still unclear. Here, we showed that acute heat stress induces mitochondrial damage and significantly increases the number of mitophagy-like vesicles in the cytoplasm of duck ovary granulosa cells at the ultra-structural level. Meanwhile, we also found heat stress significantly increased mitochondrial fission and mitophagy-related protein expression levels both in vivo and in vitro. Furthermore, by confocal fluorescence analysis, we discovered that LC3 was distributed spot-like manner near the nucleus in the heat treatment group, and the LC3 spots and lysosomes were colocalized with Mito-Tracker in the heat treatment group. We further detected the mitophagy-related protein in the cytoplasm and mitochondria, respectively. Results showed that the PINK1 protein was significantly increased both in cytoplasm and mitochondria, while the LC3-Ⅱ/LC3-Ⅰ ratio increase only occurred in mitochondrial. In addition, the autophagy protein induced by acute heat treatment was effectively inhibited by the mitophagy inhibitor CysA. Finally, we demonstrated that the alteration of cellular mitophagy by siRNA interference with Drp1 and PINK1 inhibited the steroid synthesis of granulosa cells and increased cell apoptosis. Study provides strong evidence that the Drp1 regulated PINK1-dependent mitophagy pathway protects follicular granulosa cells from acute heat stress-induced injury.

Keywords: Drp1; PINK1; granulosa cells; heat stress; mitophagy

DOI: https://doi.org/10.1016/j.psj.2023.103247

Sci Rep. 2023 Nov 23. 13(1): 20541

Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death.

Nana Yaa Nsiah, Autumn B Morgan, Nina Donkor, Denise M Inman.

Ocular hypertension during glaucoma can lead to hypoxia, activation of the HIF transcription factors, and a metabolic shift toward glycolysis. This study aims to test whether chronic HIF activation and the attendant metabolic reprogramming can initiate glaucoma-associated pathology independently of ocular hypertension. HIF-1α stabilization was induced in mice for 2 and 4 weeks by inhibiting prolyl hydroxylases using the small molecule Roxadustat. HIF-1α stabilization and the expression of its downstream bioenergetic targets were investigated in the retina by immunofluorescence, capillary electrophoresis, and biochemical enzyme activity assays. Roxadustat dosing resulted in significant stabilization of HIF-1α in the retina by 4 weeks, and upregulation in glycolysis-associated proteins (GLUT3, PDK-1) and enzyme activity in both neurons and glia. Accordingly, succinate dehydrogenase, mitochondrial marker MTCO1, and citrate synthase activity were significantly decreased at 4 weeks, while mitophagy was significantly increased. TUNEL assay showed significant apoptosis of cells in the retina, and PERG amplitude was significantly decreased with 4 weeks of HIF-1α stabilization. A significant increase in AMPK activation and glial hypertrophy, concomitant with decreases in retinal ganglion cell function and inner retina cell death suggests that chronic HIF-1α stabilization alone is detrimental to retina metabolic homeostasis and cellular survival.

DOI: https://doi.org/10.1038/s41598-023-47942-8