Regulation of mitochondrial trafficking, function and quality control by the mitochondrial GTPases Miro1 and Miro2

Abstract

MicroRNAs (miRNAs) are short, 22-25 nucleotide long transcripts that may suppress entire signaling pathways by interacting with the 3'-untranslated region (3'-UTR) of coding mRNA targets, interrupting translation and inducing degradation of these targets. The long 3'-UTRs of brain transcripts compared to other tissues predict important roles for brain miRNAs. Supporting this notion, we found that brain miRNAs co-evolved with their target transcripts, that non-coding pseudogenes with miRNA recognition elements compete with brain coding mRNAs on their miRNA interactions, and that Single Nucleotide Polymorphisms (SNPs) on such pseudogenes are enriched in mental diseases including autism and schizophrenia, but not Alzheimer's disease (AD). Focusing on evolutionarily conserved and primate-specifi c miRNA controllers of cholinergic signaling ('CholinomiRs'), we fi nd modifi ed CholinomiR levels in the brain and/or nucleated blood cells of patients with AD and Parkinson's disease, with treatment-related diff erences in their levels and prominent impact on the cognitive and anti-infl ammatory consequences of cholinergic signals. Examples include the acetylcholinesterase (AChE)-targeted evolutionarily conserved miR-132, whose levels decline drastically in the AD brain. Furthermore, we found that interruption of AChE mRNA's interaction with the primatespecifi c CholinomiR-608 in carriers of a SNP in the AChE's miR-608 binding site induces domino-like eff ects that reduce the levels of many other miR-608 targets. Young, healthy carriers of this SNP express 40% higher brain AChE activity than others, potentially aff ecting the responsiveness to AD's anti-AChE therapeutics, and show elevated trait anxiety, infl ammation and hypertension. Non-coding regions aff ecting miRNA-target interactions in neurodegenerative brains thus merit special attention.

Is Disrupted Mitophagy a Central Player to Parkinson’s Disease Pathology?

“…PINK1 has similarly been associated with mitochondrial trafficking. The OMM-bound GTPases Miro1 and Miro2 are integral to the migration of mitochondria in neurons, through a linking process attaching mitochondria to kinesin and dynein motor proteins [ 53 , 54 ]. Elevated levels of Miro are associated with dopaminergic neurone loss, but the levels can be returned to normal by increasing levels of PINK1.…”

Miro proteins and their role in mitochondrial transfer in cancer and beyond

“…It is known that Miro1 is a key regulator of mitochondrial trafficking not only in neurons but also in other cell types ( Yamaoka et al, 2011 ; Kittler, 2015 ; Stephen et al, 2015 ; Lopez-Domenech et al, 2016 ; Lopez-Domenech et al, 2018 ; Kalinski et al, 2019 ; Eberhardt et al, 2020 ; Nahacka et al, 2021 ). Both proteins were found to bind protein complexes involved in tubulin (kinesin/dynein and TRAK1/2 complex) and actin (myosin XIX or Myo19) movement, but their participation in these processes is quite different ( Brickley et al, 2005 ; Fransson et al, 2006 ; Glater et al, 2006 ; MacAskill et al, 2009a ; Lopez-Domenech et al, 2018 ; Oeding et al, 2018 ; Bocanegra et al, 2020 ).…”

“…Mitophagy is a specific type of autophagy occurring in the case of energetic disbalance and defective mitochondria ( Kittler, 2015 ; Pickles et al, 2018 ). One of the types of mitophagy was shown to be regulated by PINK1 kinase that activates Parkin, a ubiquitin ligase that ubiquitinates several downstream targets located in the OMM, including Miro proteins ( Greene et al, 2012 ; Kane et al, 2014 ; Lazarou et al, 2015 ).…”

“…Additionally Miro1 and partially Miro2 have been shown to be important for mitochondrial transport towards the cell periphery, especially in case of energy-demanding processes such as migration and invasion of cancer cells ( Caino et al, 2016 ; Lopez-Domenech et al, 2018 ; Wang et al, 2021 ). Knock-out of these two proteins results in perinuclear localization of mitochondria, with more prominent phenotype in case of Miro1/Miro2 double knock-out ( Kittler, 2015 ). It can be expected that successful displacement of mitochondria at the periphery of the donor cell is a necessary step for the process of mitochondrial transfer via TNTs; and, Miro proteins play an essential role in this process.…”

“…Mitochondria are highly dynamic organelles that constantly undergo cycles of fusion and fission, and, depending on the cellular type or metabolic status, they differ in size, shape or localization within the cell ( Berridge et al, 2016 ; Furnish and Caino, 2020 ; Nahacka et al, 2021 ). They could be efficiently transported to the site of their need, utilizing the system of molecular motors together with tubulin and actin cytoskeleton ( MacAskill and Kittler, 2010 ; Kittler, 2015 ; Eberhardt et al, 2020 ; Grossmann et al, 2020 ). Furthermore, mitochondria communicate with other organelles, often forming physical bridges with the endoplasmic reticulum (ER) or the nucleus ( Modi et al, 2019 ; Desai et al, 2020 ).…”