MDM2 and mitochondrial function: One complex intersection

Abstract

Decades of research reveal that MDM2 participates in cellular processes ranging from macro-molecular metabolism to cancer signaling mechanisms. Two recent studies uncovered a new role for MDM2 in mitochondrial bioenergetics. Through the negative regulation of NDUFS1 (NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1) and MT-ND6 (NADH dehydrogenase 6), MDM2 decreases the function and efficiency of Complex I (CI). These observations propose several important questions: (1) Where does MDM2 affect CI activity? (2) What are the cellular consequences of MDM2-mediated regulation of CI? (3) What are the physiological implications of these interactions? Here, we will address these questions and position these observations within the MDM2 literature.

Keywords: Apoptosis; Bioenergetics; Complex I; Electron transport chain; MDM2; Mitochondria; Oncogene; Tumor suppressor; p53.

Figure 1:. MDM2 gene and protein structure.

The diversity of MDM2 signaling comes from a complex gene and protein structure. Located on the long arm of chromosome 12, Mdm2 contains twelve exons and two promoters (P1 and P2). MDM2^WT consists of 491 amino acids that comprise four functional domains essential to its function. They are the amino-terminal p53 binding domain, a central acidic domain, a zinc finger region, and the RING (Really Interesting New Gene) domain, which contains E3 ubiquitin ligase activity. The amino-terminus is commonly referred to as the p53-binding domain because this is its most characterized interaction, but it is also responsible for binding a variety of other proteins (e.g., E2F1 and p73). Following the amino-terminal domain is a linker region containing both a nuclear localization signal and a nuclear export signal (NLS and NES, respectively) that regulate MDM2 subcellular localization. The central acidic domain negatively regulates the p53-signalling pathway by inducing the ubiquitination of p53 or by inducing a conformational change that inhibits p53’s transcriptional activity (Cross et al., 2011). Finally, the E3 ubiquitin ligase activity of the RING domain is responsible for regulating both subcellular localization and degradation of various MDM2 interacting proteins.

Figure 2.. The electron transport chain mantains mitochondrial respiration and generates the proton-motive gradient.

(A) Schematic diagram of Complexes I-V (CI, CII, CIII, CIV, and CV), which are integrated in the inner mitochondrial membrane (IMM). CI is the entry point for electrons (e⁻) via the oxidation of NADH to NAD⁺. These electrons flow through CI and CII to ubiquinone (Q), which is involved in the reduction of oxygen (O₂) to free radicals (O₂⁻). CII acts as a secondary electron entry point via the oxidation of FADH₂ to FAD⁺. Collectively, electrons flow from CIII to reduce cytochrome c (Cyto c), which is then utilized by CIV to reduce molecular oxygen (the final electron acceptor) to water (H₂0). CI, CIII, and CIV generate the proton motive force (Δψ_M) by pumping hydrogen ions (H⁺) from the mitochondrial matrix into the inner mitochondrial space (IMS). In turn, the H⁺ gradient generated by the electron transport chain (ETC) drives CV (ATPase synthase) to convert adenosine diphosphate and inorganic phosphate (ADP and PO_4-, respectively) into ATP. (B) Assembly of CI, CIII, and CIV into supercomplex structures, which promote efficient e⁻ transport, reduced ROS production and optimal ETC capacity.

Figure 3.. MDM2 over-expression disrupts Complex I activity through two distinct mechanisms.

Mitochondrial MDM2 binds to mitochondrial DNA leading to decreased MT-ND6 expression, Complex I activity, and induced mitochondrial fragmentation and ROS. Conversely, cytosolic MDM2 sequesters NDUFS1 in the cytosol causing supercomplex dissociation, decreased Complex I activity, increased ROS, DNA damage, and apoptosis.