Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.

Several phospholipid (PL) molecules are intertwined with some mitochondrial complex I (CI) subunits in the membrane domain of CI, but their function is unclear. We report that when the Drosophila melanogaster ortholog of the intramitochondrial PL transporter, STARD7, is severely disrupted, assembly of the oxidative phosphorylation (OXPHOS) system is impaired, and the biogenesis of several CI subcomplexes is hampered. However, intriguingly, a restrained knockdown of STARD7 impairs the incorporation of NDUFS5 and NDUFA1 into the proximal part of the CI membrane domain without directly affecting the incorporation of subunits in the distal part of the membrane domain, OXPHOS complexes already assembled, or mitochondrial cristae integrity.

Resting mitochondrial complex I from adopts a helix-locked state.

Respiratory complex I is a proton-pumping oxidoreductase key to bioenergetic metabolism. Biochemical studies have found a divide in the behavior of complex I in metazoans that aligns with the evolutionary split between Protostomia and Deuterostomia. Complex I from Deuterostomia including mammals can adopt a biochemically defined off-pathway 'deactive' state, whereas complex I from Protostomia cannot.

IDH2-mediated regulation of the biogenesis of the oxidative phosphorylation system.

Several subunits in the matrix domain of mitochondrial complex I (CI) have been posited to be redox sensors for CI, but how elevated levels of reactive oxygen species (ROS) impinge on CI assembly is unknown. We report that genetic disruption of the mitochondrial NADPH-generating enzyme, isocitrate dehydrogenase 2 (IDH2), in flight muscles results in elevated ROS levels and impairment of assembly of the oxidative phosphorylation system (OXPHOS). Mechanistically, this begins with an inhibition of biosynthesis of the matrix domain of CI and progresses to involve multiple OXPHOS complexes.

Dissecting the concordant and disparate roles of NDUFAF3 and NDUFAF4 in mitochondrial complex I biogenesis.

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 , we report that when either of the CIAFs - NDUFAF3 or NDUFAF4 - is disrupted, biogenesis of the Q-, N-, and P-modules of CI is impaired. This is due, at least in part, to the compromised integration of NDUFS3 and NDUFS5 into the Q-, and P-modules, respectively, coupled with a destabilization of another CIAF, TIMMDC1, in assembly intermediates.

An antibody toolbox to track complex I assembly defines AIF's mitochondrial function.

An ability to comprehensively track the assembly intermediates (AIs) of complex I (CI) biogenesis in Drosophila will enable the characterization of the precise mechanism(s) by which various CI regulators modulate CI assembly. Accordingly, we generated 21 novel antibodies to various mitochondrial proteins and used this resource to characterize the mechanism by which apoptosis-inducing factor (AIF) regulates CI biogenesis by tracking the AI profile observed when AIF expression is impaired. We find that when the AIF-Mia40 translocation complex is disrupted, the part of CI that transfers electrons to ubiquinone is synthesized but fails to progress in the CI biosynthetic pathway.

Insights from Drosophila on mitochondrial complex I.

NADH:ubiquinone oxidoreductase, more commonly referred to as mitochondrial complex I (CI), is the largest discrete enzyme of the oxidative phosphorylation system (OXPHOS). It is localized to the mitochondrial inner membrane. CI oxidizes NADH generated from the tricarboxylic acid cycle to NAD, in a series of redox reactions that culminates in the reduction of ubiquinone, and the transport of protons from the matrix across the inner membrane to the intermembrane space.

Gateways to the Laboratory: How an MD-PhD Program Increased the Number of Minority Physician-Scientists.

Traditional underrepresented minority (URM) groups (African Americans, Hispanic Americans, Native Americans) remain underrepresented among physician-scientists. To address the dearth of URM physician-scientists, in 1993 the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program developed a pipeline program, Gateways to the Laboratory (Gateways), which focuses on increasing the breadth and depth of the URM physician-scientist pipeline by offering an all-encompassing summer research training program which mirrors the life of a physician-scientist. This includes hypothesis-driven research and clinical shadowing opportunities, coupled with weekly career development workshops and extensive multitiered mentoring.