Abstract
Best known as the powerhouse of the cell, mitochondria have many other important functions such as buffering intracellular calcium and reactive oxygen species levels, initiating apoptosis and supporting cell proliferation and survival. Mitochondria are also dynamic organelles that are constantly undergoing fission and fusion to meet specific functional needs. These processes and functions are regulated by intracellular signaling at the mitochondria. A-kinase anchoring protein 1 (AKAP1) is a scaffold protein that recruits protein kinase A (PKA), other signaling proteins, as well as RNA to the outer mitochondrial membrane. Hence, AKAP1 can be considered a mitochondrial signaling hub. In this review, we discuss what is currently known about AKAP1′s function in health and diseases. We focus on the recent literature on AKAP1′s roles in metabolic homeostasis, cancer and cardiovascular and neurodegenerative diseases. In healthy tissues, AKAP1 has been shown to be important for driving mitochondrial respiration during exercise and for mitochondrial DNA replication and quality control. Several recent in vivo studies using AKAP1 knockout mice have elucidated the role of AKAP1 in supporting cardiovascular, lung and neuronal cell survival in the stressful post-ischemic environment. In addition, we discuss the unique involvement of AKAP1 in cancer tumor growth, metastasis and resistance to chemotherapy. Collectively, the data indicate that AKAP1 promotes cell survival throug regulating mitochondrial form and function. Lastly, we discuss the potential of targeting of AKAP1 for therapy of various disorders.
Highlights
Sutherland’s discovery of cyclic adenosine monophosphate (cAMP) in 1958 [1,2], for which he was awarded the 1971 Nobel Prize in Physiology or Medicine, the second messenger has been implicated in a multitude of cellular processes, including growth, differentiation, and survival. cAMP is synthesized from ATP by a family of adenylyl cyclases, which are regulated by heterotrimeric G proteins or Ca2+ /calmodulin in response to cell surface receptor signaling. cAMP actions are mediated by two effectors, cAMP-dependent protein kinase (PKA) and the more recently discovered guanylate exchange factor Epac [3]. cAMP signaling is terminated by the hydrolysis of cAMP to 50 -AMP by a large group of phosphodiesterases, which are themselves highly regulated [4]
A kinase anchoring proteins (AKAPs) are a group of structurally unrelated proteins that have in common the ability to bind protein kinase A (PKA) regulatory subunits with high affinity [6,7]
Several recent studies have examined the role of A-kinase anchoring protein 1 (AKAP1) in mitochondrial quality control
Summary
Signal transduction downstream of growth factors, hormones, and neurotransmitters engages second messengers including cyclic adenosine monophosphate (cAMP). Upon binding of cAMP, the two catalytic subunits are released to phosphorylate PKA substrates, eliciting downstream signaling. AKAPs are a group of structurally unrelated proteins that have in common the ability to bind PKA regulatory subunits with high affinity [6,7]. Because AKAPs interact with regulatory, rather than catalytic subunits of PKA, initiation of substrate phosphorylation still requires cAMP-mediated release of the active catalytic subunit for compartmentalized signaling within the cell. The generation of cAMP and its degradation by phosphodiesterases at the surface and inner compartments of the mitochondria has recently been reviewed [8,9]
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