Control of mitochondria dynamics and oxidative metabolism by cAMP, AKAPs and the proteasome

Mitochondria are highly specialized organelles and major players in fundamental aspects of cell physiology. In yeast, energy metabolism and coupling of mitochondrial activity to growth and survival is controlled by the protein kinase A pathway. In higher eukaryotes, modulation of the so-called A-kinase anchor protein (AKAP) complex regulates mitochondrial dynamics and activity, adapting the oxidative machinery and the metabolic pathway to changes in physiological demand. Protein kinases and phosphatases are assembled by AKAPs within transduction units, providing a mechanism to control signaling events at mitochondria and other target organelles. Ubiquitin-mediated proteolysis of signal transducers and effectors provides an additional layer of complexity in the regulation of mitochondria homeostasis. Genetic evidence indicates that alteration of one or more components of these biochemical pathways leads to mitochondrial dysfunction and human diseases. In this review, we focus on the emerging role of AKAP scaffolds and the proteasome pathway in the control of oxidative metabolism, organelle dynamics and the mitochondrial signaling network. These aspects are crucial elements for maintaining a proper energy balance and cellular lifespan.

Introduction

Mitochondria are the powerhouse of the energy-producing systems of the cell. Damage to mitochondria has a key role in aging and neurodegenerative diseases. In eukaryotic cells, energy production is functionally coupled to metabolic demands. This mechanism enables the cell to efficiently adapt oxidative respiration in response to changes in extracellular microenvironment and metabolic nutrient availability. Mitochondrial fusion and fission represent two dynamic events that have a major impact on mitochondrial activity, thus, regulating the oxidative machinery. Key regulators of mitochondrial dynamics such as mitofusins, optic atrophy type 1 (OPA1) and dynamin-related protein 1 (Drp1) have been identified and functionally characterized. Signaling events generated at the cell membrane by hormones and growth factors are also known to modulate mitochondrial activity but the molecular mechanism underlying such regulation has, so far, been elusive. Recent findings indicate that the mitochondrial response to hormones, growth factors and metabolic demands requires coordinated (space) and sequential (time) activation of intracellular signaling cascades. The concerted actions of upstream regulators and downstream effectors rapidly adapt the cell to changes in metabolic demands. This intricate biochemical apparatus, which operates in multi-cellular organisms, evolved from duplications of ancient linear unicellular systems, in which activation of signaling enzymes and adaptor molecules occurred in a single step and in the same location. Cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) evolved as an important mediator of hormone action on cellular respiration. In eukaryotic cells, PKA is concentrated in membrane and cellular organelles, including mitochondria, through interactions with A kinase anchor proteins (AKAPs). AKAPs form local signal transduction units, which include different signaling enzymes, adaptor molecules and mRNAs. The AKAP complex functions as a molecular relay that generates spatial and temporal codes of cAMP signals, optimizing phosphorylation and de-phosphorylation events on co-localized effectors and ensuring efficient propagation of signals to target sites.

Localization of signaling enzymes and AKAP scaffold proteins at the outer membrane of mitochondria indicates a role for these signals in the control of mitochondrial responses to hormone stimulation. Also, an increasing body of evidence links mitochondrial dynamics and AKAP signaling to the ubiquitin–proteasome pathway. This linkage provides a mechanism that rapidly adapts activity of the organelle to changes of metabolic demands.

In this review, we focus on the emerging unexpected connections between compartmentalized cAMP signaling and the proteasome pathway in controlling major aspects of mitochondrial network and oxidative metabolism.