bims-mitpro 2024-05-12 papers

Issue of 2024–05–12
three papers selected by
Andreas Kohler, Umeå University

FASEB J. 2024 May 15. 38(9): e23654

Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats.

Man Xu, Li-Peng Li, Xi He, Xing-Zhu Lu, Xue-Yuan Bi, Qi Li, Xiao-Rong Xue.

Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.

Keywords: cardiac remodeling; heat shock factor 1; hypertension; metformin; mitochondrial unfolded protein response

DOI: https://doi.org/10.1096/fj.202400070R

J Cell Signal. 2023 ;4(4): 151-162

Depleting Cellular Retinoic Acid Binding Protein 1 Impairs UPRmt.

Chin-Wen Wei, Thomas Lerdall, Fatimah Najjar, Li-Na Wei.

Mitochondrial dysfunction underlines neurodegenerative diseases which are mostly characterized by progressive degeneration of neurons. We previously reported that Cellular retinoic acid Binding protein 1 (Crabp1) knockout (CKO) mice spontaneously developed age-dependent motor degeneration, with defects accumulated in spinal motor neurons (MNs), the only cell type in spinal cord that expresses CRABP1. Here we uncovered that mitochondrial DNA (mtDNA) content and the expression of genes involved in respiration were significantly reduced in CKO mouse spinal cord, accompanied by significantly elevated reactive oxygen species (ROS) and unfolded protein load, indicating that CRABP1 deficiency caused mitochondrial dysfunction. Further analyses of spinal cord tissues revealed significant reduction in the expression and activity of superoxide dismutase 2 (SOD2), as well as defected mitochondrial unfolded protein response (UPRmt) pathway, specifically an increase in ATF5 mRNA but not its protein level, which suggested failure in the translational response of ATF5 in CKO. Consistently, eukaryotic initiation factor-2α, (eIF2α) phosphorylation was reduced in CKO spinal cord. In a CRABP1 knockdown MN1 model, siCrabp1-MN1, we validated the cell-autonomous function of CRABP1 in modulating the execution of UPRmt. This study reveals a new functional role for CRABP1 in the execution of mitochondrial stress response, that CRABP1 modulates eIF2α phosphorylation thereby contributing to ATF5 translational response that is needed to mitigate mitochondria stress.

Keywords: Crabp1; Reactive oxygen species; Unfolded protein response; eIF2α

DOI: https://doi.org/10.33696/signaling.4.102

bioRxiv. 2024 Apr 23. pii: 2023.06.25.546449. [Epub ahead of print]

A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

Xiaolei Liu, Sudhish A Devadiga, Robert F Stanley, Ryan Morrow, Kevin Janssen, Mathieu Quesnel-Vallières, Oz Pomp, Adam A Moverley, Chenchen Li, Nicolas Skuli, Martin P Carroll, Jian Huang, Douglas C Wallace, Kristen W Lynch, Omar Abdel-Wahab, Peter S Klein.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2 P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2 P95H -induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2 P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2 P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2 P95H mutant MDS and AML.

DOI: https://doi.org/10.1101/2023.06.25.546449