bims-mitlys 2021-09-26 papers

Issue of 2021–09–26
four papers selected by
Nicoletta Plotegher, University of Padova

J Cereb Blood Flow Metab. 2021 Sep 22. 271678X211046992

Mitochondrial quality control in acute ischemic stroke.

Mitochondria play a central role in the pathophysiological processes of acute ischemic stroke. Disruption of the cerebral blood flow during acute ischemic stroke interrupts oxygen and glucose delivery, leading to the dysfunction of mitochondrial oxidative phosphorylation and cellular bioenergetic stress. Cells can respond to such stress by activating mitochondrial quality control mechanisms, including the mitochondrial unfolded protein response, mitochondrial fission and fusion, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer. Collectively, these adaptive response strategies contribute to retaining the integrity and function of the mitochondrial network, thereby helping to recover the homeostasis of the neurovascular unit. In this review, we focus on mitochondrial quality control mechanisms occurring in acute ischemic stroke. A better understanding of how these regulatory pathways work in maintaining mitochondrial homeostasis will provide a rationale for developing innovative neuroprotectants when these mechanisms fail in acute ischemic stroke.

Keywords: Acute ischemic stroke; intercellular mitochondrial transfer; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitochondrial unfolded protein response; mitophagy

DOI: https://doi.org/10.1177/0271678X211046992

Am J Physiol Heart Circ Physiol. 2021 Sep 24.

Autophagy, TERT, and mitochondrial dysfunction in hyperoxia.

Andreas M Beyer, Laura E Norwood Toro, William E Hughes, Micaela Young, Anne V Clough, Feng Gao, Meetha Medhora, Said H Audi, Elizabeth R Jacobs.

Ventilation with gases containing enhanced fractions of oxygen is the cornerstone of therapy for patients with hypoxia and acute respiratory distress syndrome. Yet, hyperoxia treatment increases free reactive oxygen species (ROS)-induced lung injury, which is reported to disrupt autophagy/mitophagy. Altered extranuclear activity of the catalytic subunit of telomerase, TERT, plays a protective role in ROS injury and autophagy in the systemic and coronary endothelium. We investigated interactions between autophagy/mitophagy and TERT that contribute to mitochondrial dysfunction and pulmonary injury in cultured rat lung microvascular endothelial cells (RLMVECs) exposed in vitro, and rat lungs exposed in vivo to hyperoxia for 48 hours. Hyperoxia induced mitochondrial damage in rat lungs (TOMM20, MTT), which was paralleled by increased markers of inflammation (MPO, IL-1β, TLR9), impaired autophagy signaling (Beclin-1, LC3B-II/1, p62), and decreased the expression of TERT. Mitochondrial specific autophagy (mitophagy) was not altered as hyperoxia increased expression of Pink1 but not Parkin. Hyperoxia-induced mitochondrial damage (TOMM20) was more pronounced in rats that lack the catalytic subunit of TERT, and resulted in a reduction in cellular proliferation rather than cell death in RLMVECs. Activation of TERT or autophagy individually offset mitochondrial damage (MTT). Combined activation/inhibition failed to alleviate hyperoxic-induced mitochondrial damage in vitro, while activation of autophagy in vivo decreased mitochondrial damage (MTT) in both WT and rats lacking TERT. Functionally, activation of either TERT or autophagy preserved transendothelial membrane resistance. Altogether, these observations show that activation of autophagy/mitophagy and/or TERT mitigate loss of mitochondrial function and barrier integrity in hyperoxia.

Keywords: Autophagy; Lung; Mitochondria; hyperoxia; p62

DOI: https://doi.org/10.1152/ajpheart.00166.2021

Aging (Albany NY). 2021 Sep 22. 13(undefined):

Cx32 inhibits the autophagic effect of Nur77 in SH-SY5Y cells and rat brain with ischemic stroke.

Fengfeng Ping, Chao Zhang, Xue Wang, Yan Wang, Danli Zhou, Jing Hu, Yanhua Chen, Jingjing Ling, Jia Zhou.

The pathogenesis of cerebral ischemia-reperfusion (I/R) is complex. Cx32 expression has been reported to be up-regulated in ischemic lesions of aged human brain. Nevertheless, the function of Cx32 during cerebral I/R is poorly understood. Autophagy is of vital importance in the pathogenesis of cerebral I/R. In the current study, we found that oxygen-glucose deprivation/reoxygenation (OGD/R) or I/R insult significantly induced the up-regulation of Cx32 and activation of autophagy. Inhibition of Cx32 alleviated OGD/R or I/R injury, and further activated autophagy. In addition, Nur77 expression was found to be up-regulated after OGD/R or I/R. After inhibiting Cx32, the expression of Nur77 was further increased and Nur77 was translocated from nucleus to mitochondrial. Inhibition of Cx32 also activated mitophagy by promoting autophagosome formation and up-regulating the expression of mitochondrial autophagy marker molecules. Of note, in the siNur77-transfected cells, the number of dysfunctional mitochondrial was increased, and mitophagy was suppressed, which aggravated OGD/R-induced neuronal injury. In conclusion, Cx32 might act as a regulatory factor of Nur77 controlling neuronal autophagy in the brains. Understanding the mechanism of this regulatory pathway will provide new insight into the role Cx32 and Nur77 in cerebral ischemia, offering new opportunities for therapeutics.

Keywords: Cx32; Nur77; autophagy; ischemic stroke; mitophagy

DOI: https://doi.org/10.18632/aging.203526

Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00682-1. [Epub ahead of print]81(18): 3677-3690

AMPK: restoring metabolic homeostasis over space and time.

Elijah Trefts, Reuben J Shaw.

The evolution of AMPK and its homologs enabled exquisite responsivity and control of cellular energetic homeostasis. Recent work has been critical in establishing the mechanisms that determine AMPK activity, novel targets of AMPK action, and the distribution of AMPK-mediated control networks across the cellular landscape. The role of AMPK as a hub of metabolic control has led to intense interest in pharmacologic activation as a therapeutic avenue for a number of disease states, including obesity, diabetes, and cancer. As such, critical work on the compartmentalization of AMPK, its downstream targets, and the systems it influences has progressed in recent years. The variegated distribution of AMPK-mediated control of metabolic homeostasis has revealed key insights into AMPK in normal biology and future directions for AMPK-based therapeutic strategies.

DOI: https://doi.org/10.1016/j.molcel.2021.08.015