The mitochondrial rhomboid protease: Its rise from obscurity to the pinnacle of disease-relevant genes

•Mitochondrial rhomboids regulate mitochondrial biology and stress responses.•PARL-dependent substrate cleavage likely signals healthy or damaged mitochondria.•Impaired PARL function results in impaired stress responses implicated in diseases.•PARL is an important regulator of mitochondria-mediated stress responses.

The Rhomboid proteases belong to a highly conserved family of proteins that are present in all branches of life. In Drosophila, the secretory pathway-localized rhomboid proteases are crucial for epidermal growth factor (EGF) signaling. The identification of a mitochondrial-localized rhomboid protease shed light on other functions of rhomboid proteases including the maintenance of mitochondrial morphology and the regulation of apoptosis. More recent work has revealed other functions of the mitochondrial rhomboid protease in mitochondrial and cellular biology, failure of which have been implicated in human diseases. In this review, we will summarize the current knowledge and disease relevance of the mitochondrial-localized rhomboid protease. This article is part of a Special Issue entitled: Intramembrane Proteases.

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