Mitochondrial dysfunction may play an important role in the pathogenic mechanism of Huntington's disease (HD). However, the exact mechanism by which mutated huntingtin could cause bioenergetic dysfunction is still unknown. We have constructed a stable inducible yeast model of HD by expressing a human huntingtin fragment containing a mutant polyglutamine tract of 103Q fused to green fluorescent protein (GFP), and a control expressing a wild-type 25Q domain fused to GFP in a wild-type strain. We showed that in yeast cells expressing 103Q, cell respiration was progressively reduced after 4-6 h of induction with galactose, down to 50% of the control after 10 h of induction. The cell respiration defect results from an alteration in the function and amount of mitochondrial respiratory chain complex II+III, in congruency to data obtained from postmortem brain of HD patients and from toxin models. In our model, the production of reactive oxygen species (ROS) is significantly enhanced in cells expressing 103Q. Quenching of ROS with resveratrol partially prevents the cell respiration defect. Mitochondrial morphology and distribution were also altered in cells expressing 103Q, probably resulting from the interaction of aggregates with portions of the mitochondrial web and from a progressive disruption of the actin cytoskeleton. We propose a mechanism for mitochondrial dysfunction in our yeast model of HD in which the interactions of misfolded/aggregated polyglutamine domains with the mitochondrial and actin networks lead to disturbances in mitochondrial distribution and function and to increase in ROS production. Oxidative damage could preferentially affect the stability and function of enzymes containing iron-sulfur clusters such as complexes II and III. Our yeast model represents a very useful paradigm to study mitochondrial physiology alterations in the pathogenic mechanism of HD.