Impaired mitochondrial trafficking in Huntington's disease

Abstract

Impaired mitochondrial function has been well documented in Huntington's disease. Mutant huntingtin is found to affect mitochondria via various mechanisms including the dysregulation of gene transcription and impairment of mitochondrial function or trafficking. The lengthy and highly branched neuronal processes constitute complex neural networks in which there is a large demand for mitochondria-generated energy. Thus, the impaired mitochondria trafficking in neuronal cells may play an important role in the selective neuropathology of Huntington's disease. Here we discuss the evidence for the effect of the Huntington's disease protein huntingtin on the intracellular trafficking of mitochondria and the involvement of this defective trafficking in the pathogenesis of Huntington's disease.

Transcriptional dysregulation in Huntington's disease: a failure of adaptive transcriptional homeostasis

“…The simultaneous defects in clearance machineries, such as the ubiquitin-proteasome system and autophagic machinery, lead to accumulation of these misfolded proteins and/or inclusion bodies, which, in turn, further aggravates cytoplasmic stress. Concurrent with these cellular events, mHtt also causes oxidative and mitochondrial stress by impairing oxidative phosphorylation [48], Ca 2+ handling [49], mitochondrial trafficking to synapses [50] and mitochondrial ultrastructure [51]. …”

Energy deficit in Huntington disease: why it matters

“…Mutant Htt altered the distribution and reduced the transport rate of mitochondria together with lowered ATP levels in the synaptosomal fraction isolated from knockin mouse brain (97). However, the mechanisms by which mutant Htt affects intracellular organelle trafficking such as mitochondria are not fully understood (44). A recent study of HD brains identified a reduced number and altered distribution of mitochondria within vulnerable, calbindin-positive striatal neurons that was more pronounced with disease progression (98).…”

“…However, ATP depletion was directly demonstrated in HD brain tissues only recently by employing a microwave fixation system that instantly inactivates brain enzymes in rodents to preserve in vivo levels of metabolites such as ATP and phosphocreatine (40). Various mechanisms that underlie the energy deficit in HD brain have been proposed, including impaired oxidative phosphorylation (41), oxidative stress (42), impaired mitochondrial calcium handling (43), abnormal mitochondria trafficking (44), deregulation of key factors of mitochondrial biogenesis, such as the transcriptional coactivator PPARγ coactivator-1α (PGC-1α) (45), and decreased glycolysis (46). Furthermore, experimental evidence supports the view that excitatory glutaminergic inputs, which activate NMDA receptors in vulnerable medium spiny neurons, promote cell death by increasing energy demand in the setting of impaired energy capacity (47).…”

Abnormal apocrine secretory cell mitochondria in a Huntington disease patient

“…Mutant huntingtin accumulates in the outer mitochondrial membrane [1][2][3] and interferes with the transcription of mitochondrial proteins encoded by nuclear DNA [4,5]. In HD, a variety of mitochondrial function abnormalities have been described [6], including impairment in the electron transport chain [7], diminished ATP production [8], deficits in calcium homeostasis [2,9], enhanced susceptibility to mitochondrial permeability transition pore opening and to glutamate-induced excitotoxicity [10,11], impaired intracellular mitochondrial trafficking to nerve terminals [12], and dysregulation in mitochondrial fusion and fission processes [13]. Ultrastructural disturbances of mitochondria have been found in cerebral neurons [14,15], and similar mitochondrial changes have been found in HD muscle, fibroblasts, and lymphoblasts [16].…”