Dissecting the concordant and disparate roles of NDUFAF3 and NDUFAF4 in mitochondrial complex I biogenesis
Anjaneyulu Murari,
Shauna-Kay Rhooms,
Christian Garcia,
Tong Liu,
Hong Li,
Bibhuti Mishra,
Cassie Deshong,
Edward Owusu-Ansah
Affiliations
Anjaneyulu Murari
Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA
Shauna-Kay Rhooms
Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA
Christian Garcia
Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA
Tong Liu
Center for Advanced Proteomics Research, Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA
Hong Li
Center for Advanced Proteomics Research, Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University - New Jersey Medical School, Newark, NJ 07103, USA
Bibhuti Mishra
Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA
Cassie Deshong
Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA
Edward Owusu-Ansah
Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA; The Robert N. Butler Columbia Aging Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Corresponding author
Summary: Distinct sub-assemblies (modules) of mitochondrial complex I (CI) are assembled with the assistance of CI Assembly Factors (CIAFs) through mechanisms that are incompletely defined. Here, using genetic analyses in Drosophila, we report that when either of the CIAFs – NDUFAF3 or NDUFAF4 – is disrupted, biogenesis of the Q-, N-, and PP-b-modules of CI is impaired. This is due, at least in part, to the compromised integration of NDUFS3 and NDUFS5 into the Q-, and PP-b-modules, respectively, coupled with a destabilization of another CIAF, TIMMDC1, in assembly intermediates. Notably, forced expression of NDUFAF4 rescues the biogenesis defects in the Q-module and some aspects of the defects in the PP-b-module of CI when NDUFAF3 is disrupted. Altogether, our studies furnish new fundamental insights into the mechanism by which NDUFAF3 and NDUFAF4 regulate CI assembly and raises the possibility that certain point mutations in NDUFAF3 may be rescued by overexpression of NDUFAF4.
