Axonal degeneration in multiple sclerosis: the mitochondrial hypothesis

Abstract

Multiple sclerosis (MS) is a chronic disease of the central nervous system, affecting more than 2 million people worldwide. Traditionally considered an inflammatory demyelinating disease, recent evidence now points to axonal degeneration as crucial to the development of irreversible disability. Studies show that axonal degeneration occurs throughout the entire course of MS. Although the specific mechanisms causing axonal damage may differ at various stages, mitochondrial failure seems to be a common underlying theme. This review addresses the mitochondrial hypothesis for axonal degeneration in MS, highlighting the mechanisms by which mitochondrial dysfunction leads to axonal disruption in acute inflammatory lesions and the chronic axonopathy in progressive MS. Emphasis is placed on Ca(2+), free radical production, and permeability transition pore opening as key players in mitochondrial failure, axonal transport impairment, and subsequent axonal degeneration. In addition, the role of mitochondria as therapeutic targets for neuroprotection in MS is addressed.

Figure 1

Schematic representation of the mitochondrial hypothesis for axonal degeneration in multiple sclerosis. ATP—adenosine triphosphate (adenosine diphosphate plus a single phosphate [ADP + Pi]); Ca₂+c—cytoplasmic calcium; Ca₂+m—matrix calcium; CypD—cyclophilin D; CytC—cytochrome C; ETC—electron transport chain; IFN-γ—interferon-γ; iNOS—inducible nitric oxide synthase; NO—nitric oxide; O₂—superoxide; ONOO-—peroxynitrite; PTP—permeability transition pore;TNF-β—tumor necrosis factor-β.