Mitochondrial fission and mitophagy depend on cofilin-mediated actin depolymerization activity at the mitochondrial fission site

Abstract

Mitochondria fission and mitophagy are fundamentally crucial to cellular physiology and play important roles in cancer progression. Developing a comprehensive understanding of the molecular mechanism underlying mitochondrial fission and mitophagy will provide novel strategies for cancer prevention and treatment. Actin has been shown to participate in mitochondrial fission and mitophagy regulation. Cofilin is best known as an actin-depolymerizing factor. However, the molecular mechanism by which cofilin regulates mitochondrial fission and mitophagy remains largely unknown. Here we report that knockdown of cofilin attenuates and overexpression of cofilin potentiates mitochondrial fission as well as PINK1/PARK2-dependent mitophagy induced by staurosporine (STS), etoposide (ETO), and carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Cofilin-mediated-PINK1 (PTEN-induced putative kinase 1) accumulation mainly depends on its regulation of mitochondrial proteases, including peptidase mitochondrial processing beta (MPPβ), presenilin-associated rhomboid-like protease (PARL), and ATPase family gene 3-like 2 (AFG3L2), via mitochondrial membrane potential activity. We also found that the interaction and colocalization of G-actin/F-actin with cofilin at mitochondrial fission sites undergo constriction after CCCP treatment. Pretreatment with the actin polymerization inhibitor latrunculin B (LatB) increased and actin-depolymerization inhibitor jasplakinolide (Jas) decreased mitochondrial translocation of actin induced by STS, ETO, and CCCP. Both LatB and Jas abrogated CCCP-mediated mitochondrial fission and mitophagy. Our data suggest that G-actin is the actin form that is translocated to mitochondria, and the actin-depolymerization activity regulated by cofilin at the mitochondrial fission site is crucial for inducing mitochondrial fission and mitophagy.

ROCK1 activation-mediated mitochondrial translocation of Drp1 and cofilin are required for arnidiol-induced mitochondrial fission and apoptosis

“…In this study, we also found that dephosphorylation of cofilin (Ser3) is crucial for mitochondrial translocation of cofilin, mitochondrial fission, and apoptosis in arnidioltreated cells. A recent study indicated that mitochondrial translocation of cofilin is an early step in mitochondrial fission and apoptosis [13,42]. Only dephosphorylated cofilin can translocate the fission site of mitochondria, leading to mitochondrial fission and apoptosis [13].…”

Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

“…WHAMM is an attractive candidate, being recruited to early autophagosomes to promote Arp2/3 complex activity during starvation-induced non-specific autophagy (Kast et al, 2015). Since long-term CCCP incubation leads to mitophagy and an overall increase in autophagosomes (Li et al, 2018;Matsuda et al, 2010;Park et al, 2018;Tanaka et al, 2010;Vives-Bauza et al, 2010). WHAMM may also regulate actin clouds around mitochondria.…”

“…Our work provides insights into the mechanisms behind these shape changes. A number of studies suggest that depolarization-induced shape changes are the result of massive mitochondrial fragmentation, which are generally observed after mitochondria have been depolarized for an hour or longer (Duvezin-Caubet et al, 2006;Fu and Lippincott-Schwartz, 2018;Kwon et al, 2017;Li et al, 2018). However, others show that in the first 20 min of depolarization the major change in mitochondria is circularization, which is due to changes in the IMM but not the OMM (De Vos et al, 2005;Liu and Hajnoczky, 2011;Miyazono et al, 2018).…”

Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

“…WHAMM is an attractive candidate, being recruited to early autophagosomes to promote Arp2/3 complex activity during starvation-induced nonspecific autophagy (Kast et al, 2015). Because long-term CCCP incubation leads to mitophagy and an overall increase in autophagosomes (Li et al, 2018;Matsuda et al, 2010;Park et al, 2018;Tanaka et al, 2010;Vives-Bauza et al, 2010), WHAMM might also regulate actin clouds around mitochondria. JMY is another strong candidate, due to its role in autophagosome formation after cell stress (Coutts and La Thangue, 2015).…”