Peroxisomal fission is modulated by the mitochondrial Rho‐GTPases, Miro1 and Miro2

Abstract

Peroxisomes are essential for a number of cellular functions, including reactive oxygen species metabolism, fatty acid b-oxidation and lipid synthesis. To ensure optimal functionality, peroxisomal size, shape and number must be dynamically maintained; however, many aspects of how this is regulated remain poorly characterised. Here, we show that the localisation of Miro1 and Miro2-outer mitochondrial membrane proteins essential for mitochondrial trafficking-to peroxisomes is not required for basal peroxisomal distribution and long-range trafficking, but rather for the maintenance of peroxisomal size and morphology through peroxisomal fission. Mechanistically, this is achieved by Miro negatively regulating Drp1-dependent fission, a function that is shared with the mitochondria. We further find that the peroxisomal localisation of Miro is regulated by its first GTPase domain and is mediated by an interaction through its transmembrane domain with the peroxisomal-membrane protein chaperone, Pex19. Our work highlights a shared regulatory role of Miro in maintaining the morphology of both peroxisomes and mitochondria, supporting a crosstalk between peroxisomal and mitochondrial biology.

The Emerging Role of RHOT1/Miro1 in the Pathogenesis of Parkinson's Disease

“…In human cancer cells, Miro1 variants−1 and−2 were predominantly expressed, while variants−3 and−4 showed low expression levels of 10% compared to variants−1 and−2 (24). However, in contrast to this study, Covill-Cooke et al recently showed that Miro1 variants lacking exon 19 as well as Miro2 are able to localize to peroxisomes in MEFs (134).…”

“…Nevertheless, the role of Miro in peroxisomal movement was questioned later. The knockout of Miro1 or Miro2 or a double knockout of both proteins did not reveal any effect on long-range microtubule-dependent peroxisome transport in MEFs (134). Interestingly, knockout of Miro2 revealed a significant reduction in median net displacement of peroxisomes in MEFs.…”

“…Interestingly, knockout of Miro2 revealed a significant reduction in median net displacement of peroxisomes in MEFs. This short-range peroxisomal movement was independent of the integrity of the actin and microtubule cytoskeleton but followed the oscillating movements of the ER, suggesting that Miro might regulate short-range peroxisome transport via the interaction with the ER (134).…”

“…While the results of the study by Covill-Cooke suggest that the main function of Miro at peroxisomes is independent of transport, their study demonstrated a major impact of Miro on peroxisome size and number. Double knockout of Miro1 and Miro2 in MEFs caused a significant reduction in peroxisome size, accompanied by increase in peroxisome number (134). This phenotype is likely caused by an increased interaction of the fission proteins Drp1 and Fis1 at peroxisomes, indicating that Miro proteins regulate Fis1-/Drp1-dependent fission not only of mitochondria (135) but also of peroxisomes (134).…”

Miro: A molecular switch at the center of mitochondrial regulation

“…The role of Miro in peroxisome transport has been supported by another recent study, however, in this work, Miro was implicated in peroxisome fission. In fibroblasts bearing knockout mutations of Miro1, Miro2, and double knockouts, they observed the same number of long‐range peroxisomal transport events as wild‐type cells.…”