CLPP coordinates mitoribosomal assembly through the regulation of ERAL1 levels

Abstract

Despite being one of the most studied proteases in bacteria, very little is known about the role of ClpXP in mitochondria. We now present evidence that mammalian CLPP has an essential role in determining the rate of mitochondrial protein synthesis by regulating the level of mitoribosome assembly. Through a proteomic approach and the use of a catalytically inactive CLPP, we produced the first comprehensive list of possible mammalian ClpXP substrates involved in the regulation of mitochondrial translation, oxidative phosphorylation, and a number of metabolic pathways. We further show that the defect in mitoribosomal assembly is a consequence of the accumulation of ERAL1, a putative 12S rRNA chaperone, and novel ClpXP substrate. The presented data suggest that the timely removal of ERAL1 from the small ribosomal subunit is essential for the efficient maturation of the mitoribosome and a normal rate of mitochondrial translation.

Genetic diagnosis of Mendelian disorders via RNA sequencing

“…CLPP encodes a mitochondrial ATP-dependent endopeptidase34 and CLPP-deficiency causes Perrault syndrome3536 (OMIM #601119) which is overlapping with the clinical presentation of the patient investigated here including microcephaly, deafness and severe psychomotor retardation (Supplementary Note 1). Moreover, a study recently showed that Clpp−/− mice are deficient for complex IV expression37, in line with complex IV deficiency of this patient (Supplementary Fig. 5).…”

CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis

“…The acyl‐CoA dehydrogenases differ in their specificity for very long‐ (VLCAD), long‐ (LCAD), medium‐ (MCAD), and short‐chain acyl‐CoAs (SCAD) . Although both MCAD and SCAD were detected as possible CLPP substrates in the previous screen , the overall striking upregulation of VLCAD suggests it to be a likely CLPP substrate (Fig B and C). The strongest upregulation of VLCAD levels was observed in EWAT (25‐fold) in addition to low LCAD and high MCAD levels (Fig C).…”

“…To unravel the in vivo function of CLPP in mammals, we recently generated whole-body CLPP-deficient mice (Clpp À/À ) [6]. Although CLPP function seems to be necessary in some critical period during development [6], the deficiency did not influence the postnatal life span, as no changes in the median or maximal survival for both sexes of Clpp À/À mice were detected ( Fig EV1A), in contrast to a previous study on a different CLPP-deficient model that reported a strong reduction in life span to about 1 year of age [8]. Possible reasons that might account for the discrepancy could be the different techniques used to generate the CLPP-deficient mice (gene trapping versus gene targeting) or differences in the hygienic status of the animal facilities.…”

Mitochondrial adaptation in obesity is a ClpPicated business

“…ClpP deletion was shown to ameliorate the deleterious consequences of dysregulating mitochondrial translation induced by deleting mitochondrial aspartyl aminoacyl‐tRNA synthetase. As a consequence, these results demonstrated that ClpP activity is actively involved in regulating mitochondrial translation and adaptation to metabolic demands, discarding that ClpP is exclusively acting as a disposal unit to degrade dysfunctional proteins and/or regulating the mitochondrial unfolded protein response in mammals .…”