Mutant huntingtin and mitochondrial dysfunction

Abstract

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder that gradually robs affected individuals of memory, cognitive skills and normal movements. Although research has identified a single faulty gene, the huntingtin gene, as the cause of the disease, a cure remains elusive. Strong evidence indicates that mitochondrial impairment plays a key part in HD pathogenesis. Here, we highlight how mutant huntingtin (mtHtt) might cause mitochondrial dysfunction by either perturbing transcription of nuclear-encoded mitochondrial proteins or by direct interaction with the organelle and modulation of respiration, mitochondrial membrane potential and Ca(2+) buffering. In addition, we propose that mtHtt might convey its neurotoxicity by evoking defects in mitochondrial dynamics, organelle trafficking and fission and fusion, which, in turn, might result in bioenergetic failure and HD-linked neuronal dysfunction and cell death. Finally, we speculate how mitochondria might dictate selective vulnerability of long projection neurons, such as medium spiny neurons, which are particularly affected in HD.

Figure 1

mtHtt impairs mitochondrial function by transcriptional dysregulation of nuclear encoded mitochondrial proteins and by direct effects on the organelle. (1) mtHtt blocks the PGC-1α promoter via inhibition of the CREB transcriptional activator, resulting in decreased PGC-1α expression. (2) Lowered PGC-1α will decrease PPARγ-mediated expression of nuclear encoded mitochondrial proteins that are necessary for respiration and oxidative damage defense. (3) mtHtt can have direct effects on mitochondria, blocking the respiratory complex II, just as 3-NP does. Respiratory inhibition, in turn, leads to decreased energy production and ΔΨ_m as well as increased ROS generation. The bioenergetic decline caused by transcriptional deregulation and direct effects of mtHtt on mitochondria can cause increased vulnerability to excitotoxic stimuli amplification of the mitochondrial damage by Ca²⁺-mediated mitochondrial permeability transition pore (mPTP) opening.

Figure 2

ATP-dependent motor proteins, dynein and kinesin, regulate anterograde and retrograde transport of mitochondria in neurons. Htt binds to HAP1, regulating dynein and kinesin function.

Figure 3

Hypothesis that mtHtt impinges on the mitochondrial fission/fusion engine by recruitment into the DRP1/MFN complexes. Mitochondrial fusion allows mixing of metabolites and mtDNA molecules. This process may prevent manifestation of mtDNA mutations by complementation with wild-type mtDNA. mtHtt may abnormally interact with the mitochondrial fission and fusion GTPases, DRP1 or MFN, thereby preventing further mitochondrial fusion or continuous fission. This may have a profound impact on mitochondrial mobility, Ca²⁺ handling, respiration, ATP production, free radical production and mitochondrial membrane potential. It may also lead to the manifestation of mitochondrial DNA mutations and may sensitize neurons to Ca²⁺-mediated opening of the mitochondrial permeability transition pore (mPTP) and release of apoptogenic factors like cytochrome c.