Exercise and Mitochondrial Dynamics: Keeping in Shape with ROS and AMPK

Abstract

Exercise is a robust stimulus for mitochondrial adaptations in skeletal muscle which consequently plays a central role in enhancing metabolic health. Despite this, the precise molecular events that underpin these beneficial effects remain elusive. In this review, we discuss molecular signals generated during exercise leading to altered mitochondrial morphology and dynamics. In particular, we focus on the interdependence between reactive oxygen species (ROS) and redox homeostasis, the sensing of cellular bioenergetic status via 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK), and the regulation of mitochondrial fission and fusion. Precisely how exercise regulates the network of these responses and their effects on mitochondrial dynamics is not fully understood at present. We highlight the limitations that exist with the techniques currently available, and discuss novel molecular tools to potentially advance the fields of redox biology and mitochondrial bioenergetics. Ultimately, a greater understanding of these processes may lead to novel mitochondria-targeted therapeutic strategies to augment or mimic exercise in order to attenuate or reverse pathophysiology.

Keywords: dynamics; energetics; exercise; mitochondria; oxidative stress; reactive oxygen species; redox signaling.

Figure 1

Overview of key proteins involved in mitochondrial fission and fusion. Fission processes depicted in orange: dynamin-related protein-1 (DRP1) can bind to a range of receptor proteins mitochondrial fission factor (MFF), mitochondrial fission 1 protein (FIS1), and mitochondrial dynamics proteins of 49 and 51 kDa (MID49/51) on the outer mitochondrial membrane. Upon guanosine triphosphate (GTP) hydrolysis, DRP1 oligomers constrict to divide mitochondria into separate organelles. Fusion processes depicted in blue: GTPase mitofusin (MFN1/2) of separate mitochondria dimerize, and then pull together upon GTP hydrolysis to fuse the outer mitochondrial membranes (OMM). The inner mitochondrial membrane (IMM) is fused by the binding of optic atrophy-1 (OPA1) which faces the intermembrane space (IMS) while tethered to the IMM of each incoming mitochondria. Regulation of IMM fusion occurs via proteases metalloendopeptidase mitochondrial (OMA) and ATP-dependent zinc metalloprotease 1 (YME1L) which cleave the membrane tethered domain of OPA1 from the IMM, rendering it non-functional. GDP: guanosine diphosphate.

Figure 2

Regulatory responses of mitochondrial dynamics machinery to exogenous vs. endogenous reactive oxygen species (ROS) in the form of superoxide (O₂•⁻) and/or hydrogen peroxide (H₂O₂). Exogenous H₂O₂ application (often used experimentally at supraphysiologic concentrations) leads to fragmentation via the activation of DRP1 via phosphorylation at Ser616 and also a mitoNEET dependent mechanism. Endogenous ROS generated in specific microdomains such as sites within the electron transport system (ETS), NADPH oxidase (NOX) or xanthine oxidase (XO) enzymes target numerous redox active cysteine residues contained within both fission and fusion proteins via S-glutathionylation (protein–SSG), disulfide bond formation (S–S), and S-nitrosation (protein–SNO) post-translational modifications. This allows precise control of mitochondrial dynamics in response to spatial and temporal changes in ROS. GSSG: oxidized glutathione; GSH: reduced glutathione; GRX: glutaredoxin; SOD: superoxide dismutase.

Figure 3

Known and putative roles of 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) and ROS mediated regulation of mitochondrial dynamics processes. Under energetically stressful conditions, rising AMP levels relative to ATP are sensed by AMPK which leads to the phosphorylation of downstream targets including: MFF to promote DRP1 binding, unc-51 like autophagy activating kinase (ULK) to induce mitophagy, and A-kinase anchoring protein mitochondrial (AKAP1) to bind cyclic-AMP-dependent protein kinase (PKA), leading to the inhibitory phosphorylation of DRP1 Ser637. In addition, ROS may modulate AMPK via AMP:ATP levels, extracellular signal-regulated kinase (ERK1/2) mediated phosphorylation, and additionally via glutaredoxin (GRX) mediated S-glutathionylation. However, the redox regulation of AMPK has not been experimentally shown to directly modulate fission/fusion dynamics.

Figure 4

Proposed effects of exercise on mitochondrial dynamics via AMPK and ROS linked mechanisms. Exercise of distinct mode, volume, and intensity may have differential effects on cellular perturbations. This includes an increased bioenergetic demand resulting in an increased AMP:ATP ratio, along with increased contraction mediated and post-exercise ROS formation. These perturbations are sensed by AMPK, which initiates a cascade of phosphorylation signaling events that are interlinked with redox mediated post translational modifications. The specific activation or inhibition of each fission (depicted in orange) or fusion (depicted in blue) effector results in a net mitochondrial dynamics response which allows the myocyte to better meet the localized bioenergetic requirements of subsequent energetic stress.

Figure 5

Proposed model for the interdependent regulation of mitochondrial dynamics in response to exercise.