Regulation of acid-base transporters by reactive oxygen species following mitochondrial fragmentation

Abstract

Mitochondrial morphology is determined by the balance between the opposing processes of fission and fusion, each of which is regulated by a distinct set of proteins. Abnormalities in mitochondrial dynamics have been associated with a variety of diseases, including neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and dominant optic atrophy. Although the genetic determinants of fission and fusion are well recognized, less is known about the mechanism(s) whereby altered morphology contributes to the underlying pathophysiology of these disease states. Previous work from our laboratory identified a role for mitochondrial dynamics in intracellular pH homeostasis in both mammalian cell culture and in the genetic model organism Caenorhabditis elegans. Here we show that the acidification seen in mutant animals that have lost the ability to fuse their mitochondrial inner membrane occurs through a reactive oxygen species (ROS)-dependent mechanism and can be suppressed through the use of pharmacological antioxidants targeted specifically at the mitochondrial matrix. Physiological approaches examining the activity of endogenous mammalian acid-base transport proteins in rat liver Clone 9 cells support the idea that ROS signaling to sodium-proton exchangers contributes to acidification. Because maintaining pH homeostasis is essential for cell function and viability, the results of this work provide new insight into the pathophysiology associated with the loss of inner mitochondrial membrane fusion.

Impaired Mitochondrial Dynamics and Nrf2 Signaling Contribute to Compromised Responses to Oxidative Stress in Striatal Cells Expressing Full-Length Mutant Huntingtin

“…It has been shown that mitochondria dynamically change their morphologies in response to oxidative stress [38]–[40]. Therefore, we tested whether the two striatal cell lines showed different pattern changes in mitochondrial morphology in response to H 2 O 2 .…”

Mitochondrial ROS Signaling in Organismal Homeostasis

“…Furthermore, these pathways are not limited to anti-aging responses. For example, mtROS signaling has also been implicated in other homeostatic pathways and processes, including wound healing (Xu and Chisholm, 2014), survival under hypoxia (Schieber and Chandel, 2014), intracellular pH homeostasis (Johnson et al, 2012), cell differentiation (Hamanaka and Chandel, 2010; Hamanaka et al, 2013; Tormos et al, 2011), and innate immunity (West et al, 2011). Accordingly, the remainder of this Review will be devoted to the role of mtROS in whole-body physiology, with the main focus on neuroendocrine control of systemic metabolism in mammals.…”

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

“…Thapsigargin (Abcam) (Xu et al 2001), mito-TEMPO (Sigma) (Johnson et al 2012), and cyclosporine A (Sigma) (Giacomotto et al 2013) were dissolved in DMSO and added to the NGM media (cooled to 55°) to the appropriate final concentrations, and animals were grown on these plates as previously described.…”