AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5
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AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5. / Salscheider, Silja Lucia; Gerlich, Sarah; Cabrera-Orefice, Alfredo; Peker, Esra; Rothemann, Robin Alexander; Murschall, Lena Maria; Finger, Yannik; Szczepanowska, Karolina; Ahmadi, Zeinab Alsadat; Guerrero-Castillo, Sergio; Erdogan, Alican; Becker, Mark; Ali, Muna; Habich, Markus; Petrungaro, Carmelina; Burdina, Nele; Schwarz, Guenter; Klußmann, Merlin; Neundorf, Ines; Stroud, David A; Ryan, Michael T; Trifunovic, Aleksandra; Brandt, Ulrich; Riemer, Jan.
In: EMBO J, Vol. 41, No. 17, 01.09.2022, p. e110784.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5
AU - Salscheider, Silja Lucia
AU - Gerlich, Sarah
AU - Cabrera-Orefice, Alfredo
AU - Peker, Esra
AU - Rothemann, Robin Alexander
AU - Murschall, Lena Maria
AU - Finger, Yannik
AU - Szczepanowska, Karolina
AU - Ahmadi, Zeinab Alsadat
AU - Guerrero-Castillo, Sergio
AU - Erdogan, Alican
AU - Becker, Mark
AU - Ali, Muna
AU - Habich, Markus
AU - Petrungaro, Carmelina
AU - Burdina, Nele
AU - Schwarz, Guenter
AU - Klußmann, Merlin
AU - Neundorf, Ines
AU - Stroud, David A
AU - Ryan, Michael T
AU - Trifunovic, Aleksandra
AU - Brandt, Ulrich
AU - Riemer, Jan
N1 - © 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - The mitochondrial intermembrane space protein AIFM1 has been reported to mediate the import of MIA40/CHCHD4, which forms the import receptor in the mitochondrial disulfide relay. Here, we demonstrate that AIFM1 and MIA40/CHCHD4 cooperate beyond this MIA40/CHCHD4 import. We show that AIFM1 and MIA40/CHCHD4 form a stable long-lived complex in vitro, in different cell lines, and in tissues. In HEK293 cells lacking AIFM1, levels of MIA40 are unchanged, but the protein is present in the monomeric form. Monomeric MIA40 neither efficiently interacts with nor mediates the import of specific substrates. The import defect is especially severe for NDUFS5, a subunit of complex I of the respiratory chain. As a consequence, NDUFS5 accumulates in the cytosol and undergoes rapid proteasomal degradation. Lack of mitochondrial NDUFS5 in turn results in stalling of complex I assembly. Collectively, we demonstrate that AIFM1 serves two overlapping functions: importing MIA40/CHCHD4 and constituting an integral part of the disulfide relay that ensures efficient interaction of MIA40/CHCHD4 with specific substrates.
AB - The mitochondrial intermembrane space protein AIFM1 has been reported to mediate the import of MIA40/CHCHD4, which forms the import receptor in the mitochondrial disulfide relay. Here, we demonstrate that AIFM1 and MIA40/CHCHD4 cooperate beyond this MIA40/CHCHD4 import. We show that AIFM1 and MIA40/CHCHD4 form a stable long-lived complex in vitro, in different cell lines, and in tissues. In HEK293 cells lacking AIFM1, levels of MIA40 are unchanged, but the protein is present in the monomeric form. Monomeric MIA40 neither efficiently interacts with nor mediates the import of specific substrates. The import defect is especially severe for NDUFS5, a subunit of complex I of the respiratory chain. As a consequence, NDUFS5 accumulates in the cytosol and undergoes rapid proteasomal degradation. Lack of mitochondrial NDUFS5 in turn results in stalling of complex I assembly. Collectively, we demonstrate that AIFM1 serves two overlapping functions: importing MIA40/CHCHD4 and constituting an integral part of the disulfide relay that ensures efficient interaction of MIA40/CHCHD4 with specific substrates.
KW - Apoptosis Inducing Factor/metabolism
KW - Disulfides/metabolism
KW - Electron Transport Complex I/metabolism
KW - HEK293 Cells
KW - Humans
KW - Mitochondrial Membrane Transport Proteins/genetics
KW - Mitochondrial Precursor Protein Import Complex Proteins
KW - Mitochondrial Proteins/genetics
KW - Oxidation-Reduction
KW - Protein Transport
U2 - 10.15252/embj.2022110784
DO - 10.15252/embj.2022110784
M3 - SCORING: Journal article
C2 - 35859387
VL - 41
SP - e110784
JO - EMBO J
JF - EMBO J
SN - 0261-4189
IS - 17
ER -