Coordination of mitochondrial and cellular dynamics by the actin-based motor Myo19

Abstract

Myosin XIX (Myo19) is an actin-based motor that competes with adaptors of microtubule-based motors for binding to the outer mitochondrial transmembrane proteins Miro1 and Miro2 (collectively Miro, also known as RhoT1 and RhoT2, respectively). Here, we investigate which mitochondrial and cellular processes depend on the coordination of Myo19 and microtubule-based motor activities. To this end, we created Myo19-deficient HEK293T cells. Mitochondria in these cells were not properly fragmented at mitosis and were partitioned asymmetrically to daughter cells. Respiratory functions of mitochondria were impaired and ROS generation was enhanced. On a cellular level, cell proliferation, cytokinesis and cell–matrix adhesion were negatively affected. On a molecular level, Myo19 regulates focal adhesions in interphase, and mitochondrial fusion and mitochondrially associated levels of fission protein Drp1 and adaptor proteins dynactin and TRAK1 at prometaphase. These alterations were due to a disturbed coordination of Myo19 and microtubule-based motor activities by Miro.

A Protumorigenic mDia2–MIRO1 Axis Controls Mitochondrial Positioning and Function in Cancer-Associated Fibroblasts

“…These findings are consistent with actin assembly being implicated in reorganizing and shuffling mitochondria during mitosis and mitophagy (37,51). Some of the molecular players involved in these actin-based processes are known (52), but neither mDia2's association with mitochondria nor its role in the regulation of mitochondrial distribution and function had been described. Furthermore, we discovered that mDia2 interacts with MIRO1 and that MIRO1 is essential to sustain the pro-tumorigenic activities of skin CAFs by allowing appropriate mitochondrial distribution and metabolic functions.…”

Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

“…Mitochondrial metabolism and more specifically, the relationship between OXPHOS and aerobic glycolysis plays, therefore, an important role in key cellular processes such as stemness and differentiation, but is also a defining feature during carcinogenesis. While several cytoskeletal proteins such β actin, Myosin II, or Myosin XIX have been shown to regulate mitochondrial dynamics directly (Korobova et al, 2014;Majstrowicz et al, 2021;Sato et al, 2022;Yang and Svitkina, 2019) and some of them are even present within the mitochondria (Shi et al, 2022;Xie et al, 2018), changes from OXPHOS to glycolysis are likely to require complex gene expression regulation yet to be fully understood.…”

The Multifaceted Regulation of Mitochondrial Dynamics During Mitosis

“…Myo19 depletion leads to cytokinesis failure and multinucleation likely not due to interference with the rate of mitochondrial fission and fusion, but because of misplacing mitochondria during metaphase to anaphase transition, thus generating a physical barrier against the proper assembly of the cytokinetic machinery ( Figure 5B ; Rohn et al, 2014 ). Remarkably, Myo19 is also suggested to regulate mitochondrial dynamics specifically in mitotic cells, where its deficiency leads to impaired mitochondrial fragmentation in prometaphase despite the fact that DRP1 total protein levels are elevated, further confirming the role of Myo19 in coupling mitochondrial division to mitotic progression ( Majstrowicz et al, 2021 ). The authors suggest that no difference was observed regarding the mitotic phosphorylation status of DRP1 known to regulate its pro-fission activity, however, the presence of fused mitochondria implies that future studies should address the involvement of Myo19 or in general of actin remodeling in modulating DRP1 oligomerization, interaction with its receptors and subsequent recruitment to mitotic mitochondria.…”

“…(B) Depletion of the actin-based motor protein MYO19 leads to mitochondrial misplacement which blocks the assembly of the cytokinetic machinery and results in segregation errors ( Rohn et al, 2014 ). Moreover, MYO19 is suggested to be required for the DRP1-dependent mitotic mitochondrial fragmentation ( Majstrowicz et al, 2021 ), but whether these two pathways downstream of MYO19 could be mechanistically linked remains to be investigated. (C) Disruption of the phosphorylation cascades downstream of CDK1 and AURKA leads to the continuous mitochondrial recruitment of the motor proteins Dynein and Kinesin, respectively.…”