Mitochondria control acute and chronic responses to hypoxia

Abstract

There are numerous mechanisms by which mammals respond to hypoxia. These include acute changes in pulmonary arterial tone due to smooth muscle cell contraction, acute increases in respiration triggered by the carotid body chemosensory cells, and chronic changes such as induction of red blood cell proliferation and angiogenesis by hypoxia inducible factor targets erythropoietin and vascular endothelial growth factor, respectively. Mitochondria account for the majority of oxygen consumption in the cell and have recently been appreciated to serve as signaling organelles required for the initiation or propagation of numerous homeostatic mechanisms. Mitochondria can influence cell signaling by production of reactive oxygen species and metabolites. Here we review recent evidence that mitochondrial signals can imitate acute and chronic hypoxia responses.

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

“…Thus, direct reads of proteome content suggest that individual cell types may differentially respond to mitochondria need and/or management in response to the challenges of chronic aging and acute stress insults. These results are consistent with the emerging importance of complex I and III on global cellular health during aging and its response through metabolic cascades including the TCA cycle (6,(34)(35)(36)(37)39,43,64,65).…”

“…Specifically, in mitochondrial pathways and related mitochondrial stress responsive pathways (60)(61)(62)(63), changes that are now implicated in the aging process from multiple perspectives. In particular, both complex I and complex III and their links to key metabolic pathways are asserted to be drivers of the aging process (6,(34)(35)(36)(37)39,43,64,65). Herein, we noted substantial changes in the expression of mitochondrial proteins involved in both complexes, with a marked increase in abundance of mitochondrial components in AM cells compared to AT2 cells, suggestive of cell specific differential responses reflecting their unique roles in the pathobiology of the aging process and differential response to chronic particulate and pathogen environmental stresses such as viral/bacterial challenge leading to pneumonia in the elderly and long-term impact on recovery (9).…”

“…Recently, the lifespan extending drug, metformin, was shown to protect the lung from oxidative stress by inhibiting the activity of the mitochondrial complex I leading to a reduction in reactive oxygen species (ROS) emergent from the complex I machinery (35,38,39). It is now apparent that changes in the cellular transcriptome (3,7,40), proteome (7,40), stress-related PN pathways (2,6,17,41) and mitochondrial pathways (12,(34)(35)(36)39,(42)(43)(44)(45)(46) can have complex effects on the functionality of the lung (19,(47)(48)(49)(50)(51). However, the nature of the age-associated changes that contribute to the differential sensitivity of young and old lungs to influenza and resulting pneumonia pathophysiology remain enigmatic.…”

Hypoxia Restrains Lipid Utilization via Protein Kinase A and Adipose Triglyceride Lipase Downregulation through Hypoxia-Inducible Factor

“…Although the current data suggest that the majority of hypoxic responses of lipolysis and PKA signaling would be mediated by HIF activity, it is possible that some other factor(s) also contributes to alter lipid metabolism under hypoxia. One of the potential pathways that may reduce lipolysis during fasting includes reduced mitochondrial oxidation activity (56,57). In addition, increased reactive oxygen species from mitochondria (58) or AMP-activated protein kinase (AMPK) activation (59,60) upon hypoxia may also affect lipolytic activity.…”

Acute O2 Sensing: Role of Coenzyme QH2/Q Ratio and Mitochondrial ROS Compartmentalization

“…to hypoxia in embryonic Ndufs2-deficient glomus cells is the result of a generalized disruption of mitochondrial homeostasis rather than a specific consequence of MCI dysfunction. In addition, how mitochondrial ROS production is acutely modulated by physiological hypoxia in O 2 -sensitive cells remains a subject of debate (Michelakis et al, 2004;Waypa et al, 2010;McElroy and Chandel, 2017). To address these fundamental questions, we explored the mechanisms of acute O 2 sensing in adult mice after inducible Ndufs2 deletion and chemical regeneration of NAD + as an electron acceptor.…”