Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress

Abstract

SUMMARY The mitochondrial inner membrane proteases YME1L and OMA1 are critical regulators of essential mitochondrial functions including inner membrane proteostasis maintenance and mitochondrial dynamics. Here, we show that YME1L and OMA1 are reciprocally degraded in response to distinct types of cellular stress. OMA1 is degraded through a YME1L-dependent mechanism in response to toxic insults that depolarize the mitochondrial membrane. Alternatively, insults that depolarize mitochondria and deplete cellular ATP stabilize active OMA1 and promote YME1L degradation. We show that the differential degradation of YME1L and OMA1 alters their proteolytic processing of the dynamin-like GTPase OPA1, a critical regulator of mitochondrial inner membrane morphology, which influences the recovery of tubular mitochondria following membrane depolarization-induced fragmentation. Our results reveal the differential stress-induced degradation of YME1L and OMA1 as a mechanism to sensitively adapt mitochondrial inner membrane protease activity and function in response to distinct types of cellular insults.

Structure of the mitochondrial inner membrane AAA+ protease YME1 gives insight into substrate processing

“…S7A), suggesting that increased hydrophobicity of the central pore may have evolved to improve the enzyme’s grip on greasy regions located within the numerous endogenous transmembrane substrates previously reported to be pulled out of the membrane by YME1 (44, 57, 58). Furthermore, the increased structural flexibility of YME1 oligomers observed in the absence of nucleotide, which results from the loss of inter-subunit coordination, provides an explanation for the stress-induced proteolytic degradation of YME1L1 associated with reduced nucleotide levels that can impact recovery from ischemic reperfusion in mice (10-12). The atomic description of how the AAA+ ATPase domains engage substrates will guide future studies aimed at unveiling the mechanisms that endow mitochondrial IM AAA+ proteases to act either as site-specific proteases or through processive degradation, and thereby regulate mitochondrial activity and morphology.…”

Engineered AAA+ proteases reveal principles of proteolysis at the mitochondrial inner membrane

“…However, the motif F-h-h-F (h=hydrophobic) was identified in 21 of the 127 listed human IMS proteins (Supplementary Table 1), including two confirmed substrates of YME1L: the inner membrane protease OMA1 (ref. 52; FVVF) at a position in a predicted transmembrane region; and the N terminus of the lipid carrier protein PRLD1 (FAAF)53.…”

OPA1 processing in cell death and disease – the long and short of it

“…the recovery of L-OPA1 forms and a restoration of mitochondrial morphology upon stress conclusion . Notably, OMA1 was recently found to be degraded by YME1L in depolarized mitochondria containing high levels of ATP (Rainbolt et al, 2016), suggesting that proteolysis of OMA1 can be regulated differently in different physiological contexts. The stress-induced degradation of OMA1 and of YME1L is thus emerging as an important feature of the adaptive and reversible regulation of mitochondrial dynamics.…”