Wounding triggers MIRO-1 dependent mitochondrial fragmentation that accelerates epidermal wound closure through oxidative signaling

Abstract

Organisms respond to tissue damage through the upregulation of protective responses which restore tissue structure and metabolic function. Mitochondria are key sources of intracellular oxidative metabolic signals that maintain cellular homeostasis. Here we report that tissue and cellular wounding triggers rapid and reversible mitochondrial fragmentation. Elevated mitochondrial fragmentation either in fzo-1 fusion-defective mutants or after acute drug treatment accelerates actin-based wound closure. Wounding triggered mitochondrial fragmentation is independent of the GTPase DRP-1 but acts via the mitochondrial Rho GTPase MIRO-1 and cytosolic Ca2+. The fragmented mitochondria and accelerated wound closure of fzo-1 mutants are dependent on MIRO-1 function. Genetic and transcriptomic analyzes show that enhanced mitochondrial fragmentation accelerates wound closure via the upregulation of mtROS and Cytochrome P450. Our results reveal how mitochondrial dynamics respond to cellular and tissue injury and promote tissue repair.

Miro1-mediated mitochondrial positioning supports subcellular redox status

“…Mitochondrial fragmentation following plasma membrane damage increases mROS levels that lead to RhoA mediated F-actin polymerization at the injury site [ 44 ]. In experiments using C.elegans epithelial cells, the process of increased mROS at wound sites was shown to be Miro1 dependent [ 45 ]. Additional evidence for mitochondrial control over subcellular ROS levels was shown in migrating tumor cells.…”

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress

“…Similar to hyperosmotic stress, mitochondria fragmentation in adaptive conditions has been reported in other contexts; for example, mitochondria fragmentation accelerated wound healing in response to tissue injury (Fu et al, 2020), and was essential for metabolic adaptation in hypothalamic neurons for the control of systemic glucose homeostasis (Toda et al, 2016). One potential mechanism by which mitochondria fragmentation can induce an adaptive response of cells to harmful stimuli is by inhibiting inter-organelle Ca 2+ transport (Szabadkai et al, 2004), thus altering Ca 2+ signaling (Fu et al, 2020). In addition to the translational mechanisms presented here, it has been proposed that mechanical force-mediated Ca 2+ signals in response to cell shrinkage induced by hyperosmotic stress can be a potential mechanism for mitochondria fragmentation in osmoadaptation (Kim et al, 2015).…”

“…The extent of mitochondria fragmentation appeared to be proportional to stress intensity, which was mirrored by the dramatic translational reprogramming of nuclear-encoded mitochondrial genes. Similar to hyperosmotic stress, mitochondria fragmentation in adaptive conditions has been reported in other contexts; for example, mitochondria fragmentation accelerated wound healing in response to tissue injury (Fu et al, 2020), and was essential for metabolic adaptation in hypothalamic neurons for the control of systemic glucose homeostasis (Toda et al, 2016). One potential mechanism by which mitochondria fragmentation can induce an adaptive response of cells to harmful stimuli is by inhibiting inter-organelle Ca 2+ transport (Szabadkai et al, 2004), thus altering Ca 2+ signaling (Fu et al, 2020).…”

Mitochondrial Dysfunction in Astrocytes: A Role in Parkinson’s Disease?

“…These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. In this model, small interfering RNA (siRNA)-mediated knockdown of the Rho-GTPase Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics ( Fu et al, 2020 ). Whether similar processes occur in vivo in the striatum/caudate putamen is an exciting avenue of research and can point to novel therapeutic interventions.…”