Age‐Dependent Changes in the Calcium Sensitivity of Striatal Mitochondria in Mouse Models of Huntington's Disease

Abstract

Striatal and cortical mitochondria from knock-in and transgenic mutant huntingtin mice were examined for their sensitivity to calcium induction of the permeability transition, a cause of mitochondrial depolarization and ATP loss. The permeability transition has been suggested to contribute to cell death in Huntington's Disease. Mitochondria were examined from slowly progressing knock-in mouse models with different length polyglutarnine expansions (Q20, Q50, Q92, Q111) and from the rapidly progressing transgenic R6/2 mice overexpressing exon I of human huntingtin with more than 110 polyglutamines. As previously observed in rats, striatal mitochondria from background strain CD1 and C57BL/6 control mice were more sensitive to calcium than cortical mitochondria. Between 5 and 12 months in knock-in Q92 mice and between 8 and 12 weeks in knock-in Q111 mice, striatal mitochondria developed resistance, becoming equally sensitive to calcium as cortical mitochondria, while those from Q50 mice were unchanged. Cortical mitochondrial calcium sensitivity did not change. In R6/2 mice striatal and cortical mitochondria were equally resistant to Ca 2+ while striatal mitochondria from littermate controls were more susceptible.No increases in calcium sensitivity were observed in the mitochondria from Huntington's Disease (HD) mice compared to controls. Neither motor abnormalities, nor expression of cyclophilin D corresponded to the changes in mitochondrial sensitivity. Polyglutamine expansions in huntingtin produced an early increased resistance to calcium in striatal mitochondria suggesting mitochondria undergo compensatory changes in calcium sensitivity in response to the many cellular changes wrought by polyglutamine expansion.

N-Terminal Mutant Huntingtin Associates with Mitochondria and Impairs Mitochondrial Trafficking

“…Previous reports show that mutant htt can affect a variety of functional aspects of mitochondria (Panov et al, 2002;Trushina et al, 2004;Brustovetsky et al, 2005;Milakovic and Johnson, 2005;Benchoua et al, 2006;Chang et al, 2006;Oliveira et al, 2006Oliveira et al, , 2007. Impaired axonal trafficking is known to contribute to HD pathogenesis (Gunawardena et al, 2003;Szebenyi et al, 2003;Li and Li, 2006); however, it is still unclear which form of mutant htt (full-length vs truncated) is the primary cause of impaired axonal trafficking.…”

Impaired Regulation of Brain Mitochondria by Extramitochondrial Ca2+ in Transgenic Huntington Disease Rats

“…Furthermore an impaired mitochondrial function and a Ca 2ϩ dyshomeostasis were detected in PC12 cells after transfection with htt expQ plasmids (11). In contrast, increased Ca 2ϩ loading capacities were observed in brain mitochondria from several HD mice lines (12,13).…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…This idea was reinforced by the fact that CypD is upregulated in Huntington's patients and that this upregulation increased as Huntington's disease progressed (Shirendeb et al., 2011). However, other reports did not find such significant contribution of mPTP to mitochondrial injury in Huntington's disease, demonstrating that genetic inactivation of CypD does not modify the onset and the progression of the disease in mice (Brustovetsky et al., 2005; Pellman, Hamilton, Brustovetsky, & Brustovetsky, 2015; Perry et al., 2010). …”