Changes in mitochondrial morphology induced by calcium or rotenone in primary astrocytes occur predominantly through ros‐mediated remodeling

Abstract

Morphological changes in mitochondria have been primarily attributed to fission and fusion, while the more pliable transformations of mitochondria (remodeling, rounding, or stretching) have been largely overlooked. In this study, we quantify the contributions of fission and remodeling to changes in mitochondrial morphology induced by the Ca 2+ ionophore 4Br-A23187 and the metabolic toxin rotenone. We also examine the role of reactive oxygen species (ROS) in the regulation of mitochondrial remodeling. In agreement with our previous studies, mitochondrial remodeling, not fission, is the primary contributor to Ca 2+ -mediated changes in mitochondrial morphology induced by 4Br-A23187 in rat cortical astrocytes. Treatment with rotenone produced similar results. In both paradigms, remodeling was selectively blocked by antioxidants whereas fission was not, suggesting a ROS-mediated mechanism for mitochondrial remodeling. In support of this hypothesis, inhibition of endogenous ROS by overnight incubation in antioxidants resulted in elongated reticular networks of mitochondria. Examination of inner and outer mitochondrial membranes revealed that they largely acted in concert during the remodeling process. While mitochondrial morphology is traditionally ascribed to a net output of fission and fusion processes, in this study we provide evidence that the acute pliability of mitochondria can be a dominant factor in determining their morphology. More importantly, our results suggest that the remodeling process is independently regulated through a ROS-signaling mechanism.

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

“…Opposite effects of calcineurin and PKA were also reported as key events in (i) the dynamic fission-fusion events that determine the shape and function of mitochondria [162, 163], thus cell survival; (ii) neuronal output stabilization induced by tonic dopamine via type 1 dopaminergic receptors [164]; and (iii) the phosphorylation/dephosphorylation of serine 897 in the NR1 subunit of the NMDA receptor (pNR1), whose increases in phosphorylation were reported in acute morphine withdrawal [30]. …”

Mitochondrial Oxidative Stress Reduces the Immunopotency of Mesenchymal Stromal Cells in Adults With Coronary Artery Disease

“…30 Because atherosclerotic-MSCs display elevated mitochondrial oxidative stress, we next assessed the content (ie, mitochondrial mass), structure, and morphology of their mitochondria. Our results revealed that MSCs from adults with atherosclerosis have increased mitochondrial mass ( Figure 3A) and elongated mitochondria ( Figure 3B), 2 features that may reflect an increase in fusion activity.…”

The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained

“…More recent reports have attributed calcium-dependent changes in mitochondrial morphological shape to processes may be independent of Drp1-mediated mitochondrial fission (187, 188). In cortical astrocytes, treatment with a calcium ionophore, 4Br-A23187, increases intracellular calcium levels and leads to a decrease in mitochondrial length (187).…”

“…However, calcineurin inhibitors attenuate the 4Br-A23187-induced increase in mitochondrial number, suggesting that calcium-mediated changes in mitochondrial morphology can occur independently of a complete fission event. The fission-independent remodeling process is mediated through reactive oxygen species (ROS) as treatment with the antioxidant N-acetylcysteine (NAC) does not increase mitochondrial in combination with 4Br-A23187 treatment but attenuates mitochondrial length shortening (188). Therefore, it is not clear from these findings whether mitochondrial remodeling occurs independently of the canonical fission protein Drp1.…”