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

Abstract

Recent studies show that mitochondria and actin filaments work together in two contexts: (1) increased cytoplasmic calcium induces cytoplasmic actin polymerization that stimulates mitochondrial fission and (2) mitochondrial depolarization causes actin assembly around mitochondria, with roles in mitophagy. It is unclear whether these two processes utilize similar actin assembly mechanisms. Here, we show that these are distinct actin assembly mechanisms in the acute phase after treatment (<10 min). Calcium-induced actin assembly is INF2 dependent and Arp2/3 complex independent, whereas depolarizationinduced actin assembly is Arp2/3 complex dependent and INF2 independent. The two types of actin polymerization are morphologically distinct, with calcium-induced filaments throughout the cytosol and depolarization-induced filaments as 'clouds' around depolarized mitochondria. We have previously shown that calcium-induced actin stimulates increases in both mitochondrial calcium and recruitment of the dynamin GTPase Drp1 (also known as DNM1L). In contrast, depolarization-induced actin is temporally associated with extensive mitochondrial dynamics that do not result in mitochondrial fission, but in circularization of the inner mitochondrial membrane (IMM). These dynamics are dependent on the protease OMA1 and independent of Drp1. Actin cloud inhibition causes increased IMM circularization, suggesting that actin clouds limit these dynamics. This article has an associated First Person interview with the first author of the paper.

Live imaging of alterations in cellular morphology and organelles during cornification using an epidermal equivalent model

“…Several reports have shown that a cortical actin pattern is formed in differentiated keratinocytes 39,40 . Actin filaments are also known to be responsible for distributing organelles and mitochondrial depolarization [41][42][43] . Moreover, Gutowska-Owsiak et al showed that actin formed structures associated with filaggrin-containing keratohyalin granules and suggested that actin disruption accelerates keratinocyte differentiation programmes by filaggrin release from keratohyalin granules 44 .…”

Motor proteins at the mitochondria–cytoskeleton interface

“…A rapid, dynamic and transient ‘burst’ in mitochondria-localized F-actin occurs within minutes (∼5 min) of damage and requires ARP2/3 ( Fig. 3 ), but is independent of INF2 and MYO6 ( Fung et al, 2019 ; Kruppa et al, 2018 ; Li et al, 2015 ). This leads to circularization of mitochondria, which is their last chance to recover before being committed to clearance by mitophagy.…”

“…Finally, dynamic assembly and disassembly of actin filaments onto mitochondrial subpopulations has been observed at ER–mitochondria contact sites; this is blocked by inhibition of actin nucleators, such as the ARP2/3 complex and formins ( Moore et al, 2016 ). This cycling is suggested to act as a steady-state surveillance method to modulate the mitochondrial fission–fusion balance to promote network remodelling and content mixing ( Fung et al, 2019 ; Moore et al, 2016 ).…”

Structural and Functional Remodeling of Mitochondria in Cardiac Diseases

“…This process is governed by the mitochondrial protein mitochondrial Rho GTPase 1 (Miro1), a transmembrane protein consisting of two GTPase domains and two EF-hands, EF1 and EF2 (helix-loop-helix structural domain found in calcium-binding proteins) [ 27 ]. A recent study found that the distinct mechanisms regulating actin polymerization and depolarization are temporally associated with MiST [ 28 , 29 ]. Moreover, mitochondrial morphology and dynamics are partially regulated by the ER membrane contact sites (MCSs).…”