The interrelationship between mitochondrial dysfunction and transcriptional dysregulation in Huntington disease

Abstract

Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of the CAG repeat region in the huntingtin (Htt) gene. Although the pathogenic mechanisms by which mutant Htt (mHtt) causes HD have not been fully elucidated, it is becoming increasingly apparent that mHtt can impair mitochondrial function directly, as well as indirectly by dysregulation of transcriptional processes. mHtt causes increased sensitivity to Ca(2+)-induced decreases in state 3 respiration and mitochondrial permeability transition pore (mPTP) opening concurrent with a reduction in mitochondrial Ca(2+) uptake capacity. Treatment of striatal cells expressing mHtt with thapsigargin results in a decrease in mitochondrial Ca(2+) uptake and membrane potential and an increase in reactive oxygen species (ROS) production. Transcriptional processes regulated by peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator-1 alpha (PGC-1 alpha), which are critical for mitochondrial biogenesis, have been shown to be impaired in HD. In addition, the PPAR gamma signaling pathway is impaired by mHtt and the activation of this pathway ameliorates many of the mitochondrial deficits, suggesting that PPAR gamma agonists may represent an important treatment strategy for HD.

Fig. 1

Schematic Diagram of Mitochondrial Impairment Caused by Mutant Huntingtin. Mutant huntingtin (mHtt) enhances the activities of: (1) NMDA receptors (NMDARs), especially those containing NR2B subunit via increased receptor trafficking, (2) voltage-gated Ca²⁺ channels (VGCC) via association with mHtt at the cellular membrane, and (3) type 1 inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R1) via direct interaction with mHtt in the endoplasmic reticulum (ER), effects that lead to increased Ca²⁺ loading. mHtt translocates into nucleus and interferes with CREB-dependent transcriptional processes by binding to CREB-binding protein (CBP) and TBP-associated factor 4 (TAF4), which at least in part leads to transcriptional down-regulation of peroxisome proliferator-activated receptor γ (PPARα) coactivator-1α (PGC-1α). Impairment of the PGC-1α pathway by mHtt may give rise to the decreased activity of PPARγ. Since PGC-1α and PPARγ play a pivotal role in mitochondrial biogenesis and respiration, energy metabolism, thermogenesis, and detoxification of reactive oxygen species (ROS), the defects in PGC-1α/PPARγ pathway is likely in turn to contribute to mitochondrial impairment in HD. As a result of increased Ca²⁺ loading and impaired transcriptional processes, mitochondria in HD undergo functional deficits including Ca²⁺ handing defects, a decrease in ATP production, an increased sensitivity of mitochondrial membrane potential (ΔΨm) loss to Ca²⁺ loading, and a decrease in ROS defense