The mitochondrial permeability transition pore in motor neurons: Involvement in the pathobiology of ALS mice

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons (MNs) that causes paralysis. Some forms of ALS are inherited, caused by mutations in the superoxide dismutase-1 (SOD1) gene. The mechanisms of human mutant SOD1 (mSOD1) toxicity to MNs are unresolved. Mitochondria in MNs might be key sites for ALS pathogenesis, but cause-effect relationships between mSOD1 and mitochrondiopathy need further study. We used transgenic mSOD1 mice to test the hypothesis that the mitochondrial permeability transition pore (mPTP) is involved in the MN degeneration of ALS. Components of the multi-protein mPTP are expressed highly in mouse MNs, including the voltage-dependent anion channel, adenine nucleotide translocator (ANT), and cyclophilin D (CyPD), and are present in mitochondria marked by manganese SOD. MNs in pre-symptomatic mSOD1-G93A mice form swollen megamitochondria with CyPD immunoreactivity. Early disease is associated with mitochondrial cristae remodeling and matrix vesiculation in ventral horn neuron dendrites. MN cell bodies accumulate mitochondria derived from the distal axons projecting to skeletal muscle. Incipient disease in spinal cord is associated with increased oxidative and nitrative stress, indicated by protein carbonyls and nitration of CyPD and ANT. Reducing the levels of CyPD by genetic ablation significantly delays disease onset and extends the lifespan of G93A-mSOD1 mice expressing high and low levels of mutant protein in a gender-dependent pattern. These results demonstrate that mitochondria have causal roles in the disease mechanisms in MNs in ALS mice. This work defines a new mitochondrial mechanism for MN degeneration in ALS.

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

“…Indeed, CypD deletion studies show benefit in mouse models of amyloid lateral sclerosis and Parkinson's diseases as genetic ablation of CypD delayed the onset of disease and extended lifespan (Martin, Semenkow, Hanaford, & Wong, 2014; Martin et al., 2009), strengthening the role of the mPTP in the mechanisms of both diseases. The beneficial effect observed with a novel small mPTP inhibitor in a mouse model of amyloid lateral sclerosis confirmed that the mPTP could represent an interesting target for drug development in amyloid lateral sclerosis (Martin, Fancelli, et al., 2014).…”

“…mPTP opening also plays a role in the neuronal injury relevant to neurodegenerative diseases increasing in aging populations such as Alzheimer's, Parkinson's, and amyloid lateral sclerosis diseases ( Angelova & Abramov, 2017; Du et al., 2008; Gandhi et al., 2009; Martin et al., 2009 ). This is particularly true for Alzheimer's disease which is characterized by the presence of extracellular senile plaques, mainly composed of amyloid‐β (Aβ) peptide and intracellular neurofibrillary tangles made up of hyperphosphorylated tau protein (Selkoe, 2004).…”

Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency

“…We next assessed the possible role of MPTP in in vivo Pdx1 +/− β-cell death using a functional read-out, phenotypic rescue. CypD is an essential component of the MPTP, and genetic ablation of the peptidyl-prolyl isomerase (Ppif) gene encoding CypD prevents MPTP-dependent cell death (12,13,19). Accordingly, we crossed Pdx1 +/− mice, which have a well-described phenotype of glucose intolerance associated with decreased β-cell mass (4,(8)(9)(10)16), onto the homozygous Ppif −/− background.…”

“…Finally, opening of the mitochondrial permeability transition pore (MPTP) is the irreversible step in programmed necrosis. The latter process plays an important role in the pathogenesis of Alzheimer's disease and amyotrophic lateral sclerosis (12,13).…”

Mechanisms of non-apoptotic programmed cell death in diabetes and heart failure

“…Chronic diseases in which MPTP-dependent programmed cell death has been implicated include Alzheimer's disease, 30 muscular dystrophy, 31 amyotrophic lateral sclerosis, 62 heart failure, 33 and diabetes. 32 It is likely that this list will expand further.…”