Abstract
Mitochondrial protein quality control is crucial for the maintenance of correct mitochondrial homeostasis. It is ensured by several specific mitochondrial proteases located across the various mitochondrial subcompartments. Here, we focused on characterization of functional overlap and cooperativity of proteolytic subunits AFG3L2 (AFG3 Like Matrix AAA Peptidase Subunit 2) and YME1L (YME1 like ATPase) of mitochondrial inner membrane AAA (ATPases Associated with diverse cellular Activities) complexes in the maintenance of mitochondrial structure and respiratory chain integrity. We demonstrate that loss of AFG3L2 and YME1L, both alone and in combination, results in diminished cell proliferation, fragmentation of mitochondrial reticulum, altered cristae morphogenesis, and defective respiratory chain biogenesis. The double AFG3L2/YME1L knockdown cells showed marked upregulation of OPA1 protein forms, with the most prominent increase in short OPA1 (optic atrophy 1). Loss of either protease led to marked elevation in OMA1 (OMA1 zinc metallopeptidase) (60 kDa) and severe reduction in the SPG7 (paraplegin) subunit of the m-AAA complex. Loss of the YME1L subunit led to an increased Drp1 level in mitochondrial fractions. While loss of YME1L impaired biogenesis and function of complex I, knockdown of AFG3L2 mainly affected the assembly and function of complex IV. Our results suggest cooperative and partly redundant functions of AFG3L2 and YME1L in the maintenance of mitochondrial structure and respiratory chain biogenesis and stress the importance of correct proteostasis for mitochondrial integrity.
Highlights
Mitochondria are essential cellular organelles, whose function and integrity is ensured by action of quality control mechanisms, including maintenance of mitochondrial proteostasis by proteases and chaperones, ongoing mitochondrial fusion and fission events, and removal of severely damaged mitochondria by mitophagy [1,2,3]
Besides its function in the regulation of mitochondrial dynamics, YME1L is involved in the proteolytic processing of non-assembled Cox4, NDUFB6, and ND1 subunits of the mitochondrial respiratory chain [7,8]
We focused on the characterization of possible functional overlap and cooperativity of AFG3L2 and YME1L in the regulation of mitochondrial dynamics and respiratory chain biogenesis
Summary
Mitochondria are essential cellular organelles, whose function and integrity is ensured by action of quality control mechanisms, including maintenance of mitochondrial proteostasis by proteases and chaperones, ongoing mitochondrial fusion and fission events, and removal of severely damaged mitochondria by mitophagy [1,2,3]. Two ATP (adenosine triphosphate)-dependent proteolytic complexes, the m- and i-AAA (ATPases associated with various cellular activities) proteases, are found within the inner membrane of mitochondria. Mitochondrial AAA proteases are known to mediate various processes from protein quality control to regulation of mitochondrial dynamics and respiratory chain biogenesis [1,4,5,6]. Besides its function in the regulation of mitochondrial dynamics, YME1L is involved in the proteolytic processing of non-assembled Cox, NDUFB6, and ND1 subunits of the mitochondrial respiratory chain [7,8]. AFG3L2 was implicated in the processing of Cox and MT-ATP6 mitochondrially-encoded respiratory chain subunits [12,13] Both m-AAA protease subunits AFG3L2 and Spg were shown to degrade the unassembled EMRE subunit of the mitochondrial calcium uniporter complex [14]. Our results reveal cooperative and partly redundant involvement of mitochondrial AAA proteases in the maintenance of mitochondrial structure and respiratory chain biogenesis
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