Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPR^mt

Abstract

The mitochondrial matrix protease CLPP plays a central role that a strong mitochondrial cardiomyopathy and diminished respiration due to DARS2 deficiency can be alleviated by the loss of CLPP, leading to an increased de novo synthesis of individual OXPHOS subunits. These results question our current understanding of the UPR mt signaling in mammals, while introducing CLPP as a possible novel target for therapeutic intervention in mitochondrial diseases.

Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

“…Acute ischemia/hypoxia-reperfusion induces UPRmt in C. elegans [39] or endothelial cells [40] and can be a protective response. However, loss of the mitochondrial aspartyl tRNA-synthetase encoding gene DARS2 in mice results in dysregulation of mitochondrial translation and strong cardiomyopathy associated with an increase of UPRmt markers [41]. …”

Integrating the UPRmtinto the mitochondrial maintenance network

“…For example ClpP, a component required for UPR mt signaling in worms is likely dispensable for UPR mt signaling in mice and humans (Seiferling et al, 2016, Gispert et al, 2013). ClpP knockout in a DARS2 knockout model of cardiomyopathy has no effect on the induction of UPR mt genes.…”

Selektive Aktivierung der humanen caseinolytischen Protease P (ClpP)

“…Derivate mit nur einem Halogen-Substituenten an verschiedenen Positionen (3,5,8,9)z eigten ein reduziertes Aktivierungs-Potenzial. Das erste Set (1-13)u mfasst Va riationen des Benzylsubstitutions-Musters von D9.…”