Neddylation regulation of mitochondrial structure and functions

Abstract

Mitochondria are the powerhouse of a cell. The structure and function of mitochondria are precisely regulated by multiple signaling pathways. Neddylation, a post-translational modification, plays a crucial role in various cellular processes including cellular metabolism via modulating the activity, function and subcellular localization of its substrates. Recently, accumulated data demonstrated that neddylation is involved in regulation of morphology, trafficking and function of mitochondria. Mechanistic elucidation of how mitochondria is modulated by neddylation would further our understanding of mitochondrial regulation to a new level. In this review, we first briefly introduce mitochondria, then neddylation cascade, and known protein substrates subjected to neddylation modification. Next, we summarize current available data of how neddylation enzymes, its substrates (including cullins/Cullin-RING E3 ligases and non-cullins) and its inhibitor MLN4924 regulate the structure and function of mitochondria. Finally, we propose the future perspectives on this emerging and exciting field of mitochondrial research.

Keywords: Cullin-RING ligases; Energy metabolism; MLN4924; Mitochondria; Neddylation.

Fig. 1

The process of neddylation modification. a Neddylation is a process that tags the ubiquitin-like small molecule NEDD8 onto its substrate through an enzymatic cascade involving NEDD8-activating enzyme E1, NEDD8-conjugating enzyme E2 and substrate-specific NEDD8 E3 ligases. MLN4924 is a NAE inhibitor that blocks the entire neddylation pathway. b Cullin-RING ligase, consisting of a scaffold cullin, a RING protein that binds to NEDD8-loaded E2, an adaptor, and a substrate receptor, promotes ubiquitylation and degradation of their substrates. N8, NEDD8

Fig. 2

The modularity of Cullin-RING E3 ligases in mitochondria. Shown are the substrates of CRL1 (a), CRL2 (b), CRL3 (c), CRL4 (d), CRL5 (e) that are involved in the regulation of mitochondrial morphology and function

Fig. 3

MLN4924 regulates mitochondrial functions. MLN4924 induces mitochondrial fission-to-fusion conversion, increases mitochondrial copy number, oxygen consumption and ROS production, but inhibits mitochondrial membrane potential and ATP production. The proteins and signaling pathways involved in MLN4924-regulated mitochondrial functions are shown [30, 35]

Fig. 4

Proposed future directions for neddylation regulation of mitochondria. Five possible directions were proposed. See text for details