Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas

Abstract

Mitochondrial respiratory deficiencies have been observed in numerous neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. For decades, these reductions in oxidative phosphorylation (OxPhos) have been presumed to trigger an overall bioenergetic crisis in the neuron, resulting in cell death. While the connection between respiratory defects and neuronal death has never been proven, this hypothesis has been supported by the detection of nonspecific mitochondrial DNA mutations in these disorders. These findings led to the notion that mitochondrial respiratory defects could be initiators of these common neurodegenerative disorders, instead of being consequences of a prior insult, a theory we believe to be misconstrued. Herein, we review the roots of this mitochondrial hypothesis and offer a new perspective wherein mitochondria are analyzed not only from the OxPhos point of view, but also as a complex organelle residing at the epicenter of many metabolic pathways.

Figure 1. Simplified model of mitochondrial aerobic energy production (stoichiometries not implied).

The mitochondrial electron transport chain (ETC) is composed of enzymatic complexes (I–V) that transfer electrons from electron donors (NADH and FADH2) to electron acceptors embedded in the IMM via redox reactions, ultimately generating water. The ETC couples electron transport to the transfer of protons (H⁺) across the IMM, creating an electrochemical proton gradient that drives the synthesis of ATP by ATP synthase. OMM, outer mitochondrial membrane. CytC, cytochrome c; CoQ, coenzyme Q₁₀.

Figure 2. Mitochondrial metabolic network.

Many metabolic pathways converge to maintain energy output. While most cells use glucose/pyruvate for ATP synthesis, oxidation of fatty acids and amino acids can also be used in response to changes in the cellular environment and availability of substrates. These mechanisms ultimately converge onto the Krebs cycle to produce NADH and FADH₂, which in turn feed the mitochondrial ETC. Possible mechanisms of OxPhos deficiency in neurodegenerative diseases involving the AKT/PKB pathway and pyruvate metabolism are shown. G6P, glucose 6-phosphate.

Figure 3. Mitochondria-associated membrane and AD.

MAM is a specialized, lipid raft–like subdomain of the ER that communicates with mitochondria. APP is processed first by β-secretase in endosomes to produce C99. C99 then translocates to the ER (by an unknown mechanism), where it is cleaved rapidly by MAM-localized γ-secretase. In AD, however, this process is impaired, leading to the abnormal accumulation of C99 in the MAM, which correlates with increased conversion of sphingomyelin to ceramide via an upregulation of sphingomyelinase activity. In turn, the elevated ceramide compromises ETC assembly and ATP production.