Mitochondrial stress and the pathogenesis of diabetic neuropathy

Abstract

Diabetic neuropathy is a major complication of diabetes that affects the sensory and autonomic nervous systems and leads to significant morbidity and impact on quality of life of patients. Mitochondrial stress has been proposed as a major mediator of neurodegeneration in diabetes. This review briefly summarizes the nature of sensory and autonomic nerve dysfunction and presents these findings in the context of diabetes-induced nerve degeneration mediated by alterations in mitochondrial ultrastructure, physiology and trafficking. Diabetes-induced dysfunction in calcium homeostasis is discussed at length and causative associations with sub-optimal mitochondrial physiology are developed. It is clear that across a range of complications of diabetes that mitochondrial physiology is impaired, in general a reduction in electron transport chain capability is apparent. This abnormal activity may predispose mitochondria to generate elevated reactive oxygen species (ROS), although experimental proof remains lacking, but more importantly will deleteriously alter the bioenergetic status of neurons. It is proposed that the next five years of research should focus on identifying changes in mitochondrial phenotype and associated cellular impact, identifying sources of ROS in neurons and analyzing mitochondrial trafficking under diabetic conditions.

Figure 1

Mitochondriopathy in diabetic mouse prevertebral sympathetic ganglia A–C) Dilated dendrites (arrows, A) containing large numbers of mitochondria which are smaller than those of an adjacent normal perikaryon (arrows, B). Mitochondria, which may form pure aggregates, are occasionally admixed with multivesicular/autophagic bodies (arrows, C) (Akita mouse celiac ganglion, original magnification: A - 10,000X; B,C - 25,000X). D) Some pale dendritic processes contain small mitochondria, tubulovesicular elements and little rough endoplasmic reticulum (Akita mouse celiac ganglion, original magnification: 10,000X). E) A degenerating neuron containing large membranous aggregates and minute hyperchromatic mitochondria represents a recent finding in murine models, particularly the Akita mouse (Akita mouse celiac ganglion, original magnification: 3000X)

Figure 2

Scheme outlining putative mechanisms whereby the diabetic state modulates mitochondrial function and axon degeneration. Reductions in growth factors or hyperglycemia combine to alter mitochondrial bioenergetics. High intracellular [glucose] in neurons may cause a general down-regulation of ETC components, possibly through the Crabtree effect, and involving the AMP-activated protein kinase (AMPK) and/or peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1a) pathways. Antioxidant pathways, such as manganese superoxide dismutase (MnSOD), are also impaired through lowered NF-κB activation. In neurons these processes appear to be more active within the axonal region resulting in raised ROS [35]. The source of ROS in axons remains elusive, however, impaired ETC capacity and altered mitochondrial bioenergetics could contribute. In addition, high [glucose] may enhance aldose reductase (AR) activity and/or NADPH oxidase (NOX) to generate ROS. Elevated generation of ROS at axonal sites causes a range of molecular changes in protein function, for example, lipid peroxidation-dependent amino acid adduct formation that impacts further on mitochondrial function and trafficking. Suboptimal mitochondrial bioenergetics and trafficking will lead to axonal maintenance breaking down through lack of available energy stores. The axon, and distal aspect in particular, is very sensitive to such energy failure due to its high demand for ATP for axon treadmilling and maintaining ion fluxes.