bims-mitpro 2024-01-21 papers

bims-mitpro

Biomed News

on Mitochondrial proteostasis

Issue of 2024–01–21
nine papers selected by
Andreas Kohler, Umeå University

NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.
Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.
Stress granules affect the dual PI3K/mTOR inhibitor response by regulating the mitochondrial unfolded protein response.
Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury.
Mitochondrial defects triggered by amg-1 mutation elicit UPRmt and phagocytic clearance during spermatogenesis in C. elegans.
USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons.
Mitophagy in hypertension-mediated organ damage.
Loss of the WDR23 proteostasis impacts mitochondrial homeostasis in the mouse brain.
mt-tRNAs in the polymerase gamma mutant heart.

Nat Commun. 2024 Jan 16. 15(1): 546

NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations.

Liang Yang, Zifeng Ruan, Xiaobing Lin, Hao Wang, Yanmin Xin, Haite Tang, Zhijuan Hu, Yunhao Zhou, Yi Wu, Junwei Wang, Dajiang Qin, Gang Lu, Kerry M Loomes, Wai-Yee Chan, Xingguo Liu.

Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is known about how accumulated mtDNA mutations modulate intestinal homeostasis. We observe the accumulation of mtDNA mutations in the small intestine of aged male mice, suggesting an association with physiological intestinal aging. Using polymerase gamma (POLG) mutator mice and wild-type mice, we generate male mice with progressive mtDNA mutation burdens. Investigation utilizing organoid technology and in vivo intestinal stem cell labeling reveals decreased colony formation efficiency of intestinal crypts and LGR5-expressing intestinal stem cells in response to a threshold mtDNA mutation burden. Mechanistically, increased mtDNA mutation burden exacerbates the aging phenotype of the small intestine through ATF5 dependent mitochondrial unfolded protein response (UPRmt) activation. This aging phenotype is reversed by supplementation with the NAD+ precursor, NMN. Thus, we uncover a NAD+ dependent UPRmt triggered by mtDNA mutations that regulates the intestinal aging.

DOI: https://doi.org/10.1038/s41467-024-44808-z
Cell Death Differ. 2024 Jan 18.

Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.

Elena Marchesan, Alice Nardin, Sofia Mauri, Greta Bernardo, Vivek Chander, Simone Di Paola, Monica Chinellato, Sophia von Stockum, Joy Chakraborty, Stephanie Herkenne, Valentina Basso, Emilie Schrepfer, Oriano Marin, Laura Cendron, Diego L Medina, Luca Scorrano, Elena Ziviani.

Selective removal of dysfunctional mitochondria via autophagy is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to damaged mitochondria, and it requires the Serine/Threonine-protein kinase PINK1. In a coordinated set of events, PINK1 operates upstream of Parkin in a linear pathway that leads to the phosphorylation of Parkin, Ubiquitin, and Parkin mitochondrial substrates, to promote ubiquitination of outer mitochondrial membrane proteins. Ubiquitin-decorated mitochondria are selectively recruiting autophagy receptors, which are required to terminate the organelle via autophagy. In this work, we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin to Parkin translocation and Parkin-dependent mitophagy. Calcineurin downregulation or genetic inhibition prevents Parkin translocation to CCCP-treated mitochondria and impairs stress-induced mitophagy, whereas Calcineurin activation promotes Parkin mitochondrial recruitment and basal mitophagy. Calcineurin interacts with Parkin, and promotes Parkin translocation in the absence of PINK1, but requires PINK1 expression to execute mitophagy in MEF cells. Genetic activation of Calcineurin in vivo boosts basal mitophagy in neurons and corrects locomotor dysfunction and mitochondrial respiratory defects of a Drosophila model of impaired mitochondrial functions. Our study identifies Calcineurin as a novel key player in the regulation of Parkin translocation and mitophagy.

DOI: https://doi.org/10.1038/s41418-023-01251-9
Cancer Cell Int. 2024 Jan 18. 24(1): 38

Stress granules affect the dual PI3K/mTOR inhibitor response by regulating the mitochondrial unfolded protein response.

Nan Lin, Liankun Sun, Jiannan Chai, Hang Qi, Yuanxin Zhao, Jiaoyan Ma, Meihui Xia, Xiaoqing Hu.

Drug resistance remains a challenge in ovarian cancer. In addition to aberrant activation of relevant signaling pathways, the adaptive stress response is emerging as a new spotlight of drug resistance in cancer cells. Stress granules (SGs) are one of the most important features of the adaptive stress response, and there is increasing evidence that SGs promote drug resistance in cancer cells. In the present study, we compared two types of ovarian cancer cells, A2780 and SKOV3, using the dual PI3K/mTOR inhibitor, PKI-402. We found that SGs were formed and SGs could intercept the signaling factor ATF5 and regulate the mitochondrial unfolded protein response (UPRmt) in A2780 cells. Therefore, exploring the network formed between SGs and membrane-bound organelles, such as mitochondria, which may provide a new insight into the mechanisms of antitumor drug functions.

DOI: https://doi.org/10.1186/s12935-024-03210-x
Cell Stress Chaperones. 2023 Nov;pii: S1355-8145(24)00026-9. [Epub ahead of print]28(6): 675-688

Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury.

Tong Wang, Xinwei Wang, Tong Fu, Yanchun Ma, Qi Wang, Shuxiang Zhang, Xiao Zhang, Hao Zhou, Xing Chang, Ying Tong.

  Myocardial microvessels are composed of a monolayer of endothelial cells, which play a crucial role in maintaining vascular barrier function, luminal latency, vascular tone, and myocardial perfusion. Endothelial dysfunction is a key factor in the development of cardiac microvascular injury and diabetic cardiomyopathy. In addition to their role in glucose oxidation and energy metabolism, mitochondria also participate in non-metabolic processes such as apoptosis, intracellular ion handling, and redox balancing. Mitochondrial dynamics and mitophagy are responsible for regulating the quality and quantity of mitochondria in response to hyperglycemia. However, these endogenous homeostatic mechanisms can both preserve and/or disrupt non-metabolic mitochondrial functions during diabetic endothelial damage and cardiac microvascular injury. This review provides an overview of the molecular features and regulatory mechanisms of mitochondrial dynamics and mitophagy. Furthermore, we summarize findings from various investigations that suggest abnormal mitochondrial dynamics and defective mitophagy contribute to the development of diabetic endothelial dysfunction and myocardial microvascular injury. Finally, we discuss different therapeutic strategies aimed at improving endothelial homeostasis and cardiac microvascular function through the enhancement of mitochondrial dynamics and mitophagy.

Keywords:  Cardiac microvascular injury; Diabetes; Endothelial cells; Mitochondrial dynamics; Mitophagy

DOI:  https://doi.org/10.1007/s12192-023-01384-3
Development. 2024 Jan 12. pii: dev.202165. [Epub ahead of print]

Mitochondrial defects triggered by amg-1 mutation elicit UPRmt and phagocytic clearance during spermatogenesis in C. elegans.

Peng Wang, Lianwan Chen, Ning Wang, Long Miao, Yanmei Zhao.

  Mitochondria are the powerhouses of many biological processes. During spermatogenesis, post-transcriptional regulation of mitochondrial gene expression is mediated by nuclear-encoded mitochondrial RNA-binding proteins (mtRBPs). We identified AMG-1 as an mtRBP required for reproductive success in C. elegans. amg-1 mutation led to defects in mitochondrial structure and sperm budding, resulting in mitochondria being discarded into residual bodies (RBs), which ultimately delayed spermatogenesis in the proximal gonad. In addition, mitochondrial defects triggered the gonadal mitochondrial unfolded protein response and phagocytic clearance to ensure spermatogenesis but ultimately failed to rescue hermaphroditic fertility. These findings reveal a previously undiscovered role for AMG-1 in regulating C. elegans spermatogenesis, in which mitochondrial-damaged sperm prevented the transmission of defective mitochondria to mature sperm by budding and phagocytic clearance, which may also exist in the reproductive systems of higher organisms.

Keywords:   Caenorhabditis elegans ; Mitochondria; Mitochondrial unfolded protein response; Phagocytic clearance; Sperm

DOI:  https://doi.org/10.1242/dev.202165
Cell Death Dis. 2024 Jan 15. 15(1): 52

USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons.

Justyna Okarmus, Jette Bach Agergaard, Tina C Stummann, Henriette Haukedal, Malene Ambjørn, Kristine K Freude, Karina Fog, Morten Meyer.

Ubiquitination of mitochondrial proteins plays an important role in the cellular regulation of mitophagy. The E3 ubiquitin ligase parkin (encoded by PARK2) and the ubiquitin-specific protease 30 (USP30) have both been reported to regulate the ubiquitination of outer mitochondrial proteins and thereby mitophagy. Loss of E3 ligase activity is thought to be pathogenic in both sporadic and inherited Parkinson's disease (PD), with loss-of-function mutations in PARK2 being the most frequent cause of autosomal recessive PD. The aim of the present study was to evaluate whether mitophagy induced by USP30 inhibition provides a functional rescue in isogenic human induced pluripotent stem cell-derived dopaminergic neurons with and without PARK2 knockout (KO). Our data show that healthy neurons responded to CCCP-induced mitochondrial damage by clearing the impaired mitochondria and that this process was accelerated by USP30 inhibition. Parkin-deficient neurons showed an impaired mitophagic response to the CCCP challenge, although mitochondrial ubiquitination was enhanced. USP30 inhibition promoted mitophagy in PARK2 KO neurons, independently of whether left in basal conditions or treated with CCCP. In PARK2 KO, as in control neurons, USP30 inhibition balanced oxidative stress levels by reducing excessive production of reactive oxygen species. Interestingly, non-dopaminergic neurons were the main driver of the beneficial effects of USP30 inhibition. Our findings demonstrate that USP30 inhibition is a promising approach to boost mitophagy and improve cellular health, also in parkin-deficient cells, and support the potential relevance of USP30 inhibitors as a novel therapeutic approach in diseases with a need to combat neuronal stress mediated by impaired mitochondria.

DOI: https://doi.org/10.1038/s41419-024-06439-6
Front Cardiovasc Med. 2023 ;10 1309863

Mitophagy in hypertension-mediated organ damage.

Yulong Ma, Xunjie Zhou, Mingtai Gui, Lei Yao, Jianhua Li, Xiaozhe Chen, Mingzhu Wang, Bo Lu, Deyu Fu.

  Hypertension constitutes a pervasive chronic ailment on a global scale, frequently inflicting damage upon vital organs, such as the heart, blood vessels, kidneys, brain, and others. And this is a complex clinical dilemma that requires immediate attention. The mitochondria assume a crucial function in the generation of energy, and it is of utmost importance to eliminate any malfunctioning or surplus mitochondria to uphold intracellular homeostasis. Mitophagy is considered a classic example of selective autophagy, an important component of mitochondrial quality control, and is closely associated with many physiological and pathological processes. The ubiquitin-dependent pathway, facilitated by PINK1/Parkin, along with the ubiquitin-independent pathway, orchestrated by receptor proteins such as BNIP3, NIX, and FUNDC1, represent the extensively investigated mechanisms underlying mitophagy. In recent years, research has increasingly shown that mitophagy plays an important role in organ damage associated with hypertension. Exploring the molecular mechanisms of mitophagy in hypertension-mediated organ damage could represent a critical avenue for future research in the development of innovative therapeutic modalities. Therefore, this article provides a comprehensive review of the impact of mitophagy on organ damage due to hypertension.

Keywords:  hypertension; mitochondria; mitochondrial quality control; mitophagy; organ damage

DOI:  https://doi.org/10.3389/fcvm.2023.1309863
Cell Signal. 2024 Jan 17. pii: S0898-6568(24)00029-9. [Epub ahead of print] 111061

Loss of the WDR23 proteostasis impacts mitochondrial homeostasis in the mouse brain.

Chatrawee Duangjan, Ronald W Irwin, Sean P Curran.

  Mitochondrial adaptation is important for stress resistance throughout life. Here we show that WDR23 loss results in an enrichment for genes regulated by nuclear respiratory factor 1 (NRF1), which coordinates mitochondrial biogenesis and respiratory functions, and an increased steady state level of several nuclear coded mitochondrial resident proteins in the brain. Wdr23KO also increases the endogenous levels of insulin degrading enzyme (IDE) and the relaxin-3 peptide (RLN3), both of which have established roles in mediating mitochondrial metabolic and oxidative stress responses. Taken together, these studies reveal an important role for WDR23 as a component of the mitochondrial homeostat in the murine brain.

Keywords:  Complex I; Homeostasis; Mitochondria; Wdr23; hippocampus

DOI:  https://doi.org/10.1016/j.cellsig.2024.111061
J Cardiovasc Aging. 2023 Oct;pii: 41. [Epub ahead of print]3(4):

mt-tRNAs in the polymerase gamma mutant heart.

M Bilal Bayazit, Ashley Francois, Erin McGrail, Federica Accornero, Matthew S Stratton.

   Introduction: Mice harboring a D257A mutation in the proofreading domain of the mitochondrial DNA polymerase, Polymerase Gamma (POLG), experience severe metabolic dysfunction and display hallmarks of accelerated aging. We previously reported a mitochondrial unfolded protein response (UPTmt) - like (UPRmt-like) gene and protein expression pattern in the right ventricular tissue of POLG mutant mice.
Aim: We sought to determine if POLG mutation altered the expression of genes encoded by the mitochondria in a way that might also reduce proteotoxic stress.
Methods and Results: The expression of genes encoded by the mitochondrial DNA was interrogated via RNA-seq and northern blot analysis. A striking, location-dependent effect was seen in the expression of mitochondrial-encoded tRNAs in the POLG mutant as assayed by RNA-seq. These expression changes were negatively correlated with the tRNA partner amino acid's amyloidogenic potential. Direct measurement by northern blot was conducted on candidate mt-tRNAs identified from the RNA-seq. This analysis confirmed reduced expression of MT-TY in the POLG mutant but failed to show increased expression of MT-TP, which was dramatically increased in the RNA-seq data.
Conclusion: We conclude that reduced expression of amyloid-associated mt-tRNAs is another indication of adaptive response to severe mitochondrial dysfunction in the POLG mutant. Incongruence between RNA-seq and northern blot measurement of MT-TP expression points towards the existence of mt-tRNA post-transcriptional modification regulation in the POLG mutant that alters either polyA capture or cDNA synthesis in RNA-seq library generation. Together, these data suggest that 1) evolution has distributed mt-tRNAs across the circular mitochondrial genome to allow chromosomal location-dependent mt-tRNA regulation (either by expression or PTM) and 2) this regulation is cognizant of the tRNA partner amino acid's amyloidogenic properties.

Keywords:  Cardiac aging; POLG; UPRMT; mt-tRNA

DOI:  https://doi.org/10.20517/jca.2023.26