Mitochondrial trafficking in neurons and the role of the Miro family of GTPase proteins

Abstract

Correct mitochondrial dynamics are essential to neuronal function. These dynamics include mitochondrial trafficking and quality-control systems that maintain a precisely distributed and healthy mitochondrial network, so that local energy demands or Ca2+-buffering requirements within the intricate architecture of the neuron can be met. Mitochondria make use of molecular machinery that couples these organelles to microtubule-based transport via kinesin and dynein motors, facilitating the required long-range movements. These motors in turn are associated with a variety of adaptor proteins allowing additional regulation of the complex dynamics demonstrated by these organelles. Over recent years, a number of new motor and adaptor proteins have been added to a growing list of components implicated in mitochondrial trafficking and distribution. Yet, there are major questions that remain to be addressed about the regulation of mitochondrial transport complexes. One of the core components of this machinery, the mitochondrial Rho GTPases Miro1 (mitochondrial Rho 1) and Miro2 have received special attention due to their Ca2+-sensing and GTPase abilities, marking Miro an exceptional candidate for co-ordinating mitochondrial dynamics and intracellular signalling pathways. In the present paper, we discuss the wealth of literature regarding Miro-mediated mitochondrial transport in neurons and recently highlighted involvement of Miro proteins in mitochondrial turnover, emerging as a key process affected in neurodegeneration.

Mitochondrial dynamics in neuronal injury, development and plasticity

“…Neurons are especially sensitive to perturbations in mitochondrial transport given the length and complexity of their axons and dendrites. As such, aberrant mitochondrial transport results in deficits in ATP production, which is important for neurotransmitter synthesis, vesicular recycling and maintenance of the membrane potential (Birsa et al, 2013;Brodin et al, 1999;Saxton and Hollenbeck, 2012). Mitochondrial transport along microtubules is a Ca 2+ -sensitive process; here, the mitochondrial adaptor proteins of the Miro family serve as Ca 2+ sensors that regulate the interaction of mitochondria with members of the trafficking kinesin protein (TRAK)/Milton family of motor adaptors and the motor protein kinesin-1 (Tang, 2015;Lee and Lu, 2014;Lin and Sheng, 2015;Sheng, 2014).…”

Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

“…Subcellular fractionation experiments suggested that this protein localizes at least in mitochondria. Although the precise function of TPPP in mitochondria is completely unknown to date, it may be possible that TPPP plays a role as a mitochondrial motor protein, considering its binding capacity to tubulin [40]. Similar to other mitochondrial membrane proteins such as MFN1, MFN2 or DRP1 [29,41], TPPP demonstrates GTPase activity in the presence of zinc [9] and magnesium [21] ions, suggesting its multiple roles in physiological dynamics (for example, signal transduction).…”

Multippel sklerose – en mitokondriemediert sykdom?

“…Det er kjent at Ca ++ -nivået spiller en viktig rolle i de dynamiske forholdene innad i aksonet (20,22). Svikt i Na + /K + -ATPaseaktivitet som følge av demyelinisering og økt Na + -konsentrasjon intraaksonalt kan videre reversere Na + /Ca ++ -pumpen og medføre opphopning av intraaksonalt Ca ++ (23).…”