Shaping the role of mitochondria in the pathogenesis of Huntington's disease

Abstract

Intense research on the pathogenesis of Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, revealed multiple potential mechanisms, among which mitochondrial alterations had emerged as key determinants of the natural history of the disease. Pharmacological and genetic animal models of mitochondrial dysfunction in the striatum, which is mostly affected in HD corroborated a key role for these organelles in the pathogenesis of the disease. Here, we will give an account of the recent evidence indicating that the mitochondria-shaping machinery is altered in HD models and patients. Since its correction can counteract HD mitochondrial dysfunction and cellular damage, drugs impacting on mitochondrial shape are emerging as a new possibility of treatment for this devastating condition.

Figure 1

Functional alterations in HD mitochondria. The cartoon depicts the functional alterations occurring at the level of mitochondrial function, opening of the PTP, and morphology in the context of HD. Mutated Huntingtin can act at the transcriptional level, by inhibiting PGC1α, directly at the mitochondrial level, by increasing the open probability of the PTP and affecting mitochondrial respiratory chain, and at the level of DRP1 causing fragmentation and remodelling of the mitochondrial cristae.

Figure 2

Morphological alterations in HD mitochondria. Top, normal mitochondrial morphology (immunofluorescence image of TOM20 in mouse striatal precursor cells) and ultrastructure (electron microscopy of mitochondria in the same striatal precursors) in healthy striatal precursors. Bottom, fragmentation and cristae disorganization in striatal precursors cells from a mouse model of knockin of a 111 repeat polyglutamine, triggered by the cascade of events depicted. For details, please refer to Costa et al (2010).