Abstract
In the current model of mitochondrial trafficking, Miro1 and Miro2 Rho‐GTPases regulate mitochondrial transport along microtubules by linking mitochondria to kinesin and dynein motors. By generating Miro1/2 double‐knockout mouse embryos and single‐ and double‐knockout embryonic fibroblasts, we demonstrate the essential and non‐redundant roles of Miro proteins for embryonic development and subcellular mitochondrial distribution. Unexpectedly, the TRAK1 and TRAK2 motor protein adaptors can still localise to the outer mitochondrial membrane to drive anterograde mitochondrial motility in Miro1/2 double‐knockout cells. In contrast, we show that TRAK2‐mediated retrograde mitochondrial transport is Miro1‐dependent. Interestingly, we find that Miro is critical for recruiting and stabilising the mitochondrial myosin Myo19 on the mitochondria for coupling mitochondria to the actin cytoskeleton. Moreover, Miro depletion during PINK1/Parkin‐dependent mitophagy can also drive a loss of mitochondrial Myo19 upon mitochondrial damage. Finally, aberrant positioning of mitochondria in Miro1/2 double‐knockout cells leads to disruption of correct mitochondrial segregation during mitosis. Thus, Miro proteins can fine‐tune actin‐ and tubulin‐dependent mitochondrial motility and positioning, to regulate key cellular functions such as cell proliferation.
Highlights
Mitochondria are critical for ATP provision and play other essential roles in cells such as buffering calcium and lipid synthesis (MacAskill & Kittler, 2010; Sheng & Cai, 2012; Mishra & Chan, 2014)
We recently showed that Miro1 knockout (Miro1KO) animals die perinatally while Miro2 knockout (Miro2KO) animals were found to develop normally (Fig EV1A) and be viable until adulthood (LopezDomenech et al, 2016)
Due to the high homology between Miro1 and Miro2 (Fransson et al, 2003), it is conceivable that both proteins show some degree of compensation, and we wanted to investigate the consequences of deleting both Miro proteins on embryonic development
Summary
Mitochondria are critical for ATP provision and play other essential roles in cells such as buffering calcium and lipid synthesis (MacAskill & Kittler, 2010; Sheng & Cai, 2012; Mishra & Chan, 2014). The outer mitochondrial membrane (OMM) Miro (mitochondrial Rho) GTPases and the TRAK motor adaptors have emerged as key regulators of mitochondrial trafficking and distribution by coupling mitochondria to the kinesin- and dynein-dependent microtubule transport pathways (Stowers et al, 2002; Fransson et al, 2006; Birsa et al, 2013; van Spronsen et al, 2013). The prevailing model proposes that Miro proteins regulate trafficking by acting as the essential receptors for mitochondrial recruitment of the TRAK adaptors to drive kinesinand dynein-mediated movements (MacAskill & Kittler, 2010; Saxton & Hollenbeck, 2012; Schwarz, 2013; Maeder et al, 2014; Mishra & Chan, 2014; Sheng, 2014).
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