bims-mikwok 2021-11-28 papers

Issue of 2021–11–28
five papers selected by
Avinash N. Mukkala, University of Toronto

Life (Basel). 2021 Oct 21. pii: 1123. [Epub ahead of print]11(11):

Mitochondrial Quality Control in Cardiac-Conditioning Strategies against Ischemia-Reperfusion Injury.

Wylly Ramsés García-Niño, Cecilia Zazueta, Mabel Buelna-Chontal, Alejandro Silva-Palacios.

Mitochondria are the central target of ischemic preconditioning and postconditioning cardioprotective strategies, which consist of either the application of brief intermittent ischemia/reperfusion (I/R) cycles or the administration of pharmacological agents. Such strategies reduce cardiac I/R injury by activating protective signaling pathways that prevent the exacerbated production of reactive oxygen/nitrogen species, inhibit opening of mitochondrial permeability transition pore and reduce apoptosis, maintaining normal mitochondrial function. Cardioprotection also involves the activation of mitochondrial quality control (MQC) processes, which replace defective mitochondria or eliminate mitochondrial debris, preserving the structure and function of the network of these organelles, and consequently ensuring homeostasis and survival of cardiomyocytes. Such processes include mitochondrial biogenesis, fission, fusion, mitophagy and mitochondrial-controlled cell death. This review updates recent advances in MQC mechanisms that are activated in the protection conferred by different cardiac conditioning interventions. Furthermore, the role of extracellular vesicles in mitochondrial protection and turnover of these organelles will be discussed. It is concluded that modulation of MQC mechanisms and recognition of mitochondrial targets could provide a potential and selective therapeutic approach for I/R-induced mitochondrial dysfunction.

Keywords: apoptosis; autophagy; cardioprotection; exosomes; ischemic postconditioning; ischemic preconditioning; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; myocardial infarction

DOI: https://doi.org/10.3390/life11111123

Autophagy. 2021 Nov 23. 1-2

The PINK1 advantage: recycling mitochondria in times of trouble?

Zak Doric, Huihui Li, Ken Nakamura.

Parkinson disease remains a debilitating neurodegenerative disorder, despite the discovery of multiple causative genes that account for familial forms. Prominent among these are PRKN/Parkin and PINK1, whose protein products participate in mitochondrial turnover, or mitophagy. But our poor understanding of the basic biological mechanisms driven by those genes in neurons limits our ability to target them therapeutically. Here, we summarize our recent findings enabled by a new platform to track individual mitochondria in neurons. Our analysis delineates the steps of PINK1- and PRKN-dependent mitochondrial turnover, including the unexplored fates of mitochondria after fusion with lysosomes. These studies reveal unexpected mechanisms of mitochondrial quality control, which may contribute to the reliance of neurons on PINK1 under conditions of stress.

Keywords: Mitophagy; PARKIN; PINK1; Parkinson’s disease; mitochondrial turnover

DOI: https://doi.org/10.1080/15548627.2021.1998872

Redox Biol. 2021 Nov 11. pii: S2213-2317(21)00346-3. [Epub ahead of print]48 102186

A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy.

Akbar Zeb, Vinay Choubey, Ruby Gupta, Malle Kuum, Dzhamilja Safiulina, Annika Vaarmann, Nana Gogichaishvili, Mailis Liiv, Ivar Ilves, Kaido Tämm, Vladimir Veksler, Allen Kaasik.

When ROS production exceeds the cellular antioxidant capacity, the cell needs to eliminate the defective mitochondria responsible for excessive ROS production. It has been proposed that the removal of these defective mitochondria involves mitophagy, but the mechanism of this regulation remains unclear. Here, we demonstrate that moderate mitochondrial superoxide and hydrogen peroxide production oxidates KEAP1, thus breaking the interaction between this protein and PGAM5, leading to the inhibition of its proteasomal degradation. Accumulated PGAM5 interferes with the processing of the PINK1 in the mitochondria leading to the accumulation of PINK1 on the outer mitochondrial membrane. In turn, PINK1 promotes Parkin recruitment to mitochondria and sensitizes mitochondria for autophagic removal. We also demonstrate that inhibitors of the KEAP1-PGAM5 protein-protein interaction (including CPUY192018) mimic the effect of mitochondrial ROS and sensitize mitophagy machinery, suggesting that these inhibitors could be used as pharmacological regulators of mitophagy. Together, our results show that KEAP1/PGAM5 complex senses mitochondrially generated superoxide/hydrogen peroxide to induce mitophagy.

Keywords: Mitophagy; NRF2/KEAP1 pathway; Neurodegenerative diseases; Oxidative stress; PINK1/Parkin pathway

DOI: https://doi.org/10.1016/j.redox.2021.102186

Oxid Med Cell Longev. 2021 ;2021 3960773

Mitochondrial Quality Control in the Maintenance of Cardiovascular Homeostasis: The Roles and Interregulation of UPS, Mitochondrial Dynamics and Mitophagy.

Yujie Song, Yuerong Xu, Yingying Liu, Jie Gao, Lele Feng, Yuxi Zhang, Lei Shi, Miao Zhang, Dong Guo, Bingchao Qi, Mingming Zhang.

Maintenance of normal function of mitochondria is vital to the fate and health of cardiomyocytes. Mitochondrial quality control (MQC) mechanisms are essential in governing mitochondrial integrity and function. The ubiquitin-proteasome system (UPS), mitochondrial dynamics, and mitophagy are three major components of MQC. With the progress of research, our understanding of MQC mechanisms continues to deepen. Gradually, we realize that the three MQC mechanisms are not independent of each other. To the contrary, there are crosstalk among the mechanisms, which can make them interact with each other and cooperate well, forming a triangle interplay. Briefly, the UPS system can regulate the level of mitochondrial dynamic proteins and mitophagy receptors. In the process of Parkin-dependent mitophagy, the UPS is also widely activated, performing critical roles. Mitochondrial dynamics have a profound influence on mitophagy. In this review, we provide new processes of the three major MQC mechanisms in the background of cardiomyocytes and delve into the relationship between them.

DOI: https://doi.org/10.1155/2021/3960773

Sci Rep. 2021 Nov 23. 11(1): 22755

A new automated tool to quantify nucleoid distribution within mitochondrial networks.

Hema Saranya Ilamathi, Mathieu Ouellet, Rasha Sabouny, Justine Desrochers-Goyette, Matthew A Lines, Gerald Pfeffer, Timothy E Shutt, Marc Germain.

Mitochondrial DNA (mtDNA) maintenance is essential to sustain a functionally healthy population of mitochondria within cells. Proper mtDNA replication and distribution within mitochondrial networks are essential to maintain mitochondrial homeostasis. However, the fundamental basis of mtDNA segregation and distribution within mitochondrial networks is still unclear. To address these questions, we developed an algorithm, Mitomate tracker to unravel the global distribution of nucleoids within mitochondria. Using this tool, we decipher the semi-regular spacing of nucleoids across mitochondrial networks. Furthermore, we show that mitochondrial fission actively regulates mtDNA distribution by controlling the distribution of nucleoids within mitochondrial networks. Specifically, we found that primary cells bearing disease-associated mutations in the fission proteins DRP1 and MYH14 show altered nucleoid distribution, and acute enrichment of enlarged nucleoids near the nucleus. Further analysis suggests that the altered nucleoid distribution observed in the fission mutants is the result of both changes in network structure and nucleoid density. Thus, our study provides novel insights into the role of mitochondria fission in nucleoid distribution and the understanding of diseases caused by fission defects.

DOI: https://doi.org/10.1038/s41598-021-01987-9