Mitochondria: a kinase anchoring protein 1, a signaling platform for mitochondrial form and function

Abstract

Mitochondria are best known for their role as cellular power plants, but they also serve as signaling hubs, regulating cellular proliferation, differentiation, and survival. A kinase anchoring protein 1 (AKAP1) is a scaffold protein that recruits protein kinase A (PKA) and other signaling proteins, as well as RNA, to the outer mitochondrial membrane. AKAP1 thereby integrates several second messenger cascades to modulate mitochondrial function and associated physiological and pathophysiological outcomes. Here, we review what is currently known about AKAP1's macromolecular interactions in health and disease states, including obesity. We also discuss dynamin-related protein 1 (Drp1), the enzyme that catalyzes mitochondrial fission, as one of the key substrates of the PKA/AKAP1 signaling complex in neurons. Recent evidence suggests that AKAP1 has critical roles in neuronal development and survival, which are mediated by inhibitory phosphorylation of Drp1 and maintenance of mitochondrial integrity.

Keywords: Dynamin-related protein 1; Mitochondria; Mitochondrial fission; Protein kinase A; Protein phosphatases; Signal transduction.

Fig. 1

AKAP1 recruits diverse signaling proteins and mRNA to the outer mitochondrial membrane. AKAP1 is depicted in green and has an N-terminal OMM targeting sequence and C-terminal KH and Tudor domains. AKAP1 targets PKA and opposing phosphatases (CaN and PP1), and also many other signaling proteins. Additionally, AKAP1 is modified by Siah ubiquitin ligases and caspases, leading to AKAP1 degradation. Through the KH domain, AKAP1 regulates the translation of mRNAs by binding to and either enhancing (StAR, MnSOD and Fo-f) or inhibiting (LPL) translation. Abreviations – CaN, calcineurin; Casp, caspase; Drp1, dynamin related protein 1; Fo-f, ATP synthase Fo complex; KH, K homology; LPL, lipoprotein lipase; Mff, mitochondrial fission factor; MnSOD, manganese superoxide dismutase; PDE4a, phosphodiesterase type 4a; PP1, protein phosphatase 1; PTPD1, protein tyrosine phosphatase D1; Siah2, seven in absentia homolog; StAR, steroidogenic acute regulatory; TOM, transporter outer membrane; Ub, ubiquitin.