bims-mecmid 2022-03-20 papers

J Exp Clin Cancer Res. 2022 Mar 12. 41(1): 95

Inhibition of the mitochondrial protein Opa1 curtails breast cancer growth.

Margherita Zamberlan, Amandine Boeckx, Florian Muller, Federica Vinelli, Olivier Ek, Caterina Vianello, Emeline Coart, Keitaro Shibata, Aurélie Christian, Francesca Grespi, Marta Giacomello, Ingrid Struman, Luca Scorrano, Stéphanie Herkenne.

BACKGROUND: Mitochondrial fusion and fission proteins have been nominated as druggable targets in cancer. Whether their inhibition is efficacious in triple negative breast cancer (TNBC) that almost invariably develops chemoresistance is unknown.
METHODS: We used a combination of bioinformatics analyses of cancer genomic databases, genetic and pharmacological Optic Atrophy 1 (OPA1) inhibition, mitochondrial function and morphology measurements, micro-RNA (miRNA) profiling and formal epistatic analyses to address the role of OPA1 in TNBC proliferation, migration, and invasion in vitro and in vivo.
RESULTS: We identified a signature of OPA1 upregulation in breast cancer that correlates with worse prognosis. Accordingly, OPA1 inhibition could reduce breast cancer cells proliferation, migration, and invasion in vitro and in vivo. Mechanistically, while OPA1 silencing did not reduce mitochondrial respiration, it increased levels of miRNAs of the 148/152 family known to inhibit tumor growth and invasiveness. Indeed, these miRNAs were epistatic to OPA1 in the regulation of TNBC cells growth and invasiveness.
CONCLUSIONS: Our data show that targeted inhibition of the mitochondrial fusion protein OPA1 curtails TNBC growth and nominate OPA1 as a druggable target in TNBC.

DOI: https://doi.org/10.1186/s13046-022-02304-6

Front Cell Dev Biol. 2022 ;10 848214

Mitochondrial Dynamics, Mitophagy, and Mitochondria-Endoplasmic Reticulum Contact Sites Crosstalk Under Hypoxia.

Shuying Wang, Jin Tan, Yuyang Miao, Qiang Zhang.

Mitochondria are double membrane organelles within eukaryotic cells, which act as cellular power houses, depending on the continuous availability of oxygen. Nevertheless, under hypoxia, metabolic disorders disturb the steady-state of mitochondrial network, which leads to dysfunction of mitochondria, producing a large amount of reactive oxygen species that cause further damage to cells. Compelling evidence suggests that the dysfunction of mitochondria under hypoxia is linked to a wide spectrum of human diseases, including obstructive sleep apnea, diabetes, cancer and cardiovascular disorders. The functional dichotomy of mitochondria instructs the necessity of a quality-control mechanism to ensure a requisite number of functional mitochondria that are present to fit cell needs. Mitochondrial dynamics plays a central role in monitoring the condition of mitochondrial quality. The fission-fusion cycle is regulated to attain a dynamic equilibrium under normal conditions, however, it is disrupted under hypoxia, resulting in mitochondrial fission and selective removal of impaired mitochondria by mitophagy. Current researches suggest that the molecular machinery underlying these well-orchestrated processes are coordinated at mitochondria-endoplasmic reticulum contact sites. Here, we establish a holistic understanding of how mitochondrial dynamics and mitophagy are regulated at mitochondria-endoplasmic reticulum contact sites under hypoxia.

Keywords: hypoxia; mitochondria; mitochondria-endoplasmic reticulum contact sites; mitochondrial dynamics; mitophagy

DOI: https://doi.org/10.3389/fcell.2022.848214

Front Cardiovasc Med. 2021 ;8 764064

Downregulation of Uncoupling Protein 2(UCP2) Mediated by MicroRNA-762 Confers Cardioprotection and Participates in the Regulation of Dynamic Mitochondrial Homeostasis of Dynamin Related Protein1 (DRP1) After Myocardial Infarction in Mice.

Dehui Liu, Shangrong Zou, Guangnan Li, Qiyu Zhang, Chunlin Chen, Cuizhi Li, Huafeng Song, Shaoxian Chen, Jiawen Wang, Yueheng Wu, Youbin Liu.

Acute myocardial infarction (MI) is one of the leading causes of death in the world, and its pathophysiological mechanisms have not been fully elucidated. The purpose of this study was to investigate the role and mechanism of uncoupling protein 2 (UCP2) after MI in mouse heart. Here, we examined the expression and role of UCP2 in mouse heart 4 weeks after MI. The expression of UCP2 was detected by RT-PCR and western blotting. Cardiac function, myocardial fibrosis, and cardiomyocyte apoptosis were assessed by echocardiography and immunohistochemistry. Phosphatase dynamin-related protein1 (P-DRP1) and myocardial fibrosis-related proteins were measured. Cardiomyocytes were exposed to hypoxia for 6 h to mimic the model of MI. Mdivi, an inhibitor of P-DRP1, was used to inhibit DRP1-dependent mitochondrial fission. Mitochondrial superoxide, membrane potential, oxygen consumption rate, and cardiomyocyte apoptosis were detected after hypoxia. It is shown mitochondrial superoxide, membrane potential, oxygen consumption rate, and cardiomyocyte apoptosis were dependent on the level of P-DRP1. UCP2 overexpression reduced cardiomyocyte apoptosis (fibrosis), improved cardiac function and inhibit the phosphorylation of DRP1 and the ratio of P-DRP1/DRP1. However, inhibition of DRP1 by mdivi did not further reduce cell apoptosis rate and cardiac function in UCP2 overexpression group. In addition, bioinformatics analysis, luciferase activity, and western blot assay proved UCP2 was a direct target gene of microRNA-762, a up-regulated microRNA after MI. In conclusion, UCP2 plays a protective role after MI and the mechanism is involved in microRNA-762 upstream and DRP1-dependent mitochondrial fission downstream.

Keywords: DRP1; UCP2; microRNA; mitochondrial fission; myocardial infarction

DOI: https://doi.org/10.3389/fcvm.2021.764064

Mol Cell. 2022 Mar 17. pii: S1097-2765(22)00168-X. [Epub ahead of print]82(6): 1086-1088

SPOTting stress at the mitochondrial outer membrane.

Max-Hinderk Schuler, Adam L Hughes.

Li et al. (2022) discover that Toxoplasma infection triggers remodeling of the mitochondrial outer membrane through generation of a mitochondrial subdomain termed "structure positive for outer mitochondrial membrane" (SPOT).

DOI: https://doi.org/10.1016/j.molcel.2022.02.030

Sci Signal. 2022 Mar 15. 15(725): eabh1121

DNA-PKcs interacts with and phosphorylates Fis1 to induce mitochondrial fragmentation in tubular cells during acute kidney injury.

Shiyuan Wang, Hang Zhu, Ruibing Li, David Mui, Sam Toan, Xing Chang, Hao Zhou.

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) regulates cell death. We sought to determine whether DNA-PKcs played a role in the tubular damage that occurs during acute kidney injury (AKI) induced by LPS injection (to mimic sepsis), cisplatin administration, or renal ischemia/reperfusion injury. Although DNA-PKcs normally localizes to the nucleus, we detected cytoplasmic DNA-PKcs in mouse kidney tissues and urinary sediments of human patients with septic AKI. Increased cytoplasmic amounts of DNA-PKcs correlated with renal dysfunction. Tubule cell-specific DNA-PKcs deletion attenuated AKI-mediated tubular cell death and changes in the abundance of various proteins with mitochondrial functions or roles in apoptotic pathways. DNA-PKcs interacted with Fis1 and phosphorylated it at Thr34 in its TQ motif, which increased the affinity of Fis1 for Drp1 and induced mitochondrial fragmentation. Knockin mice expressing a nonphosphorylatable T34A mutant exhibited improved renal function and histological features and reduced mitochondrial fragmentation upon induction of AKI. Phosphorylation of Thr34 in Fis1 was detectable in urinary sediments of human patients with septic AKI and correlated with renal dysfunction. Our findings provide insight into the role of cytoplasmic DNA-PKcs and phosphorylated Fis1 in AKI development.

DOI: https://doi.org/10.1126/scisignal.abh1121

Cell Signal. 2022 Mar 15. pii: S0898-6568(22)00070-5. [Epub ahead of print] 110309

Sirt3 ameliorates mitochondrial dysfunction and oxidative stress through regulating mitochondrial biogenesis and dynamics in cardiomyoblast.

Paramesha Bugga, Md Jahangir Alam, Roshan Kumar, Subhashis Pal, Naibedya Chattopadyay, Sanjay Kumar Banerjee.

Sirtuins are the endogenously present anti-aging protein deacetylases that regulate the mitochondrial biogenesis and function. Especially Sirt3, a mitochondrial sirtuin, is well known for maintaining mitochondrial function and health. In the present study, we have explored the novel role of Sirt3 in mitochondrial biogenesis and shown the role of Sirt3 in mito-nuclear communication through AMPK-α in Sirt3 knockdown and Sirt3 overexpressed H9c2 cells. The study found that impaired mitochondrial function in Sirt3-knockdown H9c2 cells was associated with decreased expression of mitochondrial DNA encoded genes, reduced SOD2 expression and activity. The study also revealed that Sirt3 knockdown affects mitochondrial biogenesis and dynamics. To further confirm the role of Sirt3 on mitochondrial biogenesis and health, we did Sirt3 overexpression in H9c2 cells. Sirt3 overexpression enhanced the expression of mitochondrial DNA encoded genes, increased SOD2 activity and altered mitochondrial dynamics. Sirt3 overexpression also caused an increase in mitochondrial biogenesis gene and protein (PGC-1α and TFAM) expression. All these changes were confirmed with mitochondrial functional parameters like basal respiration, maximal respiratory capacity, spare respiratory capacity and ATP production. We found decreased mitochondrial function in Sirt3-knockdown H9c2 cells when compared to control H9c2 cells. Together our data conclude that Sirt3 regulates cardiac mitochondrial health and function through the Sirt3-AMPKα-PGC-1α axis.

Keywords: AMPK; Cardiomyoblast; Mitochondrial biogenesis; Mitochondrial dynamics; SOD2; Sirt3

DOI: https://doi.org/10.1016/j.cellsig.2022.110309