PINK1 and Parkin Control Localized Translation of Respiratory Chain Component mRNAs on Mitochondria Outer Membrane

Abstract

SUMMARY Mitochondrion plays essential roles in many aspects of biology, and its dysfunction has been linked to diverse diseases. Central to mitochondrial function is oxidative phosphorylation (OXPHOS), accomplished by respiratory chain complexes (RCCs) encoded by nuclear and mitochondrial genomes. How RCC biogenesis is regulated in metazoans is poorly understood. Here we show that Parkinson’s disease (PD)-associated genes PINK1 and Parkin direct localized translation of certain nuclear-encoded RCC (nRCC) mRNAs. Translationally-repressed nRCC mRNAs are localized in a PINK1/Tom20-dependent manner to mitochondrial outer membrane, where they are de-repressed and activated by PINK1/Parkin through displacement of translation repressors, including Pumilio and Glorund/hnRNP-F, a Parkin substrate, and enhanced binding of activators such as eIF4G. Inhibiting the translation repressors rescued nRCC mRNA translation and neuromuscular-degeneration phenotypes of PINK1 mutant, whereas inhibiting eIF4G had opposite effects. Our results reveal previously unknown functions of PINK1/Parkin in RNA metabolism and suggest new approaches to mitochondrial restoration and disease intervention.

CLUH couples mitochondrial distribution to the energetic and metabolic status

“…In our cellular model, the mtDNA abundance remained unaffected, but the mitochondrial protein synthesis was significantly reduced in the absence of CLUH, suggesting a major alteration of the mitochondrial translation process. Beside the importance of CLUH on mRNA translation of nuclear-encoded mitochondrial proteins (Gao et al, 2014;Sen and Cox, 2016), the evidence that PINK1 and Parkin also control the mRNA translation of the respiratory chain subunits at the outer mitochondrial membrane (Gehrke et al, 2015) suggests that a concerted regulation of all the respiratory components encoded by the nuclear and mitochondrial genomes can be achieved by a crosstalk between CLUH and the PINK-Parkin pathway. Thus, the decrease in the mitochondrial translation machinery in CLUH-KO cells without mtDNA defects raises questions about both the stability of mitochondrial mRNA and the regulation of specific downstream effects on the mRNAs that are targeted by CLUH (Schatton et al, 2017).…”

Localized translation near the mitochondrial outer membrane: An update

“…Studies that applied this methodology on a single-cell level have provided further support for the association of mRNAs to the mitochondrial outer membrane in both yeast 44 and Drosophila muscle tissue. 30 Finally, the recently developed proximity-specific ribosome profiling method (see below) allows the isolation and highthroughput characterization of mRNAs that are translated by mitochondria-associated ribosomes. 32 This has led to the identification of many mRNAs that are translated near the mitochondria, particularly of those that encode inner-membrane proteins.…”

“…Recent studies have revealed the molecular players that are involved in both of these modes (see Section 3). 30,31,50,51 Ribosomes' association with mitochondria can be measured by western analysis of mitochondrial fractions with an antibody that recognizes a ribosomal protein. 31,52 This technique, however, should be interpreted cautiously, as mitochondrial fractions usually contain ER fragments, which also contain ribosomes.…”

“…Nevertheless, studies from recent years have yielded novel findings regarding translation near peroxisomes, chloroplasts, the nucleus, and mitochondria. 17,28,29 In the last year few important publications [30][31][32] have provided molecular details of localized translation near the mitochondria. We cover herein data pertained to this organelle.…”

Thyroid cancer metabolism: A review

“…Lactate is then taken up by cancer cells via MCT1, a bidirectional transporter, and transported to mitochondria via a translocase of the outer mitochondrial membrane (TOMM20), leading to the generation of ATP via OXPHOS [45]. TOMM20 is a central component of the receptor complex responsible for the recognition and translocation of cytosolically-synthesized mitochondrial proteins and has been shown to be an indicator of functional mitochondrial mass and of OXPHOS activity [8,46,47]. Therefore, TOMM20, as well as MCT1, can be used as markers of OXPHOS, and MCT4 a marker of glycolytic metabolism and oxidative stress.…”