ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak

Abstract

Summary Mitochondrial distribution and motility are recognized as central to many cellular functions but their regulation by signaling mechanisms remains to be elucidated. Here we report that ROS, either derived from an extracellular source or intracellularly generated, controls mitochondrial distribution and function, by dose-dependently, specifically and reversibly decreasing mitochondrial motility in both rat hippocampal primary cultured neurons and cell lines. ROS decrease motility independently of cytoplasmic [Ca2+], mitochondrial membrane potential or permeability transition pore opening, known effectors of oxidative stress. However, multiple lines of genetic and pharmacological evidence support that a ROS-activated MAP kinase, p38α is required for the motility inhibition. Furthermore, anchoring mitochondria directly to kinesins without involvement of the physiological adaptors between the organelles and the motor protein prevents the H2O2–induced decrease in mitochondrial motility. Thus, ROS engage p38α and the motor adaptor complex to exert changes in mitochondrial motility, which likely has both physiological and pathophysiological relevance.

Causal roles of mitochondrial dynamics in longevity and healthy aging

“…Debattisti et al recently demonstrated that ROS generated from intracellular and extracellular sources can retard mitochondrial movement inside cells. Increased ROS requires p38α kinase activity in cells to inhibit the mitochondrial adaptor complex formed by proteins MIRO and TRAK, which link mitochondria to motors that allow their transport . The study shows that the cellular milieu senses increase in ROS levels and employs a specific signaling pathway to decrease mitochondrial motility.…”

Altered mitochondrial trafficking as a novel mechanism of cancer metastasis

“…For instance, ROS drive cancer motility through the actions of polarized mitochondria . Mechanistically, the ROS‐sensitive MAPK, p38, was shown to target the MIRO/TRAK complexes to decrease mitochondrial trafficking …”

“…43,76,77 Mechanistically, the ROS-sensitive MAPK, p38, was shown to target the MIRO/TRAK complexes to decrease mitochondrial trafficking. 78 Glucose fluctuations can also elicit post-translational modifications that directly affect mitochondrial movement. For instance, high extracellular glucose induced O-GlcNAcylation on the mitochondrial adapter TRAK1 in hippocampal neurons.…”

Mitochondrial-cytoskeletal interactions: dynamic associations that facilitate network function and remodeling

“…Recent work has also shown that ROS production can affect mitochondrial dynamics. Either exogenous or endogenously generated ROS inhibits mitochondrial motility in a pathway that is independent of changes in Ca 2+ , at least in mammalian cells, but is dependent on the MAP kinase p38a, potentially working through the Miro/TRAK adaptor complex [24]. Of note, the mechanism is not limited to neurons, but also affects mitochondrial motility in cardiomyocytes.…”