Comparative Studies on Mitochondria Isolated From Neuron-Enriched and Glia-Enriched Fractions of Rabbit and Beef Brain

Hamberger, Anders; Blomstrand, Christian; Lehninger, Albert L.

doi:10.1083/jcb.45.2.221

Cited by 114 publications

(20 citation statements)

References 29 publications

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“…We also observed that not all mitochondria within MNs contained CyPD, ANT, and VDAC. This observation supports that idea of that mitochondria are heterogeneous in shape (Collins and Bootman, 2003; Jensen, 2005) and biochemical composition, notably metabolism (Hamburger et al, 1970), CyPD content (Naga et al, 2007), and genetics (Wallace, 2005). …”

Section: Discussionsupporting

confidence: 89%

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

Martin

Gertz

Pan

et al. 2009

Experimental Neurology

161

244

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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.

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Section: Discussionsupporting

confidence: 89%

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

Martin

Gertz

Pan

et al. 2009

Experimental Neurology

161

244

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“…Thus, differences in the levels of individual mPTP components cannot explain the intrinsic differences in the sensitivity to Ca 2+ -induced permeability transition seen in spinal cord and brain isolated mitochondria [147, 148]. Not all mitochondria within individual MNs contained CyPD, ANT, and VDAC [78]; this observation supports that idea of that mitochondria in individual cells are not only heterogeneous in shape [149,150] but also in biochemical composition, notably metabolism [151] and genetics [36]. …”

Section: The Mitochondrial Permeability Transition Pore Contributementioning

confidence: 79%

The mitochondrial permeability transition pore: A molecular target for amyotrophic lateral sclerosis therapy

Martin

2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Effective therapies are needed for the treatment of amyotrophic lateral sclerosis (ALS), a fatal type of motor neuron disease. Morphological, biochemical, molecular genetic, and cell/animal model studies suggest that mitochondria have potentially diverse roles in neurodegenerative disease mechanisms and neuronal cell death. In human ALS, abnormalities have been found in mitochondrial structure, mitochondrial respiratory chain enzymes, and mitochondrial cell death proteins indicative of some non-classical form of programmed cell death. Mouse models of ALS are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria. This minireview summarizes work on the how malfunctioning mitochondria might contribute to neuronal death in ALS through the biophysical entity called the mitochondrial permeability pore (mPTP). The major protein components of the mPTP are enriched in mouse motor neurons. Early in the course of disease in ALS mice expressing human mutant superoxide dismutase-1, mitochondria in motor neurons undergo trafficking abnormalities and dramatic remodeling resulting in the formation of mega-mitochondria and coinciding with increased protein carbonyl formation and nitration of mPTP components. The genetic deletion of a major mPTP component, cyclophilin D, has robust effects in ALS mice by delaying disease onset and extending survival. Thus, attention should be directed to the mPTP as rational target for the development of drugs designed to treat ALS.

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“…Thus, differences in the levels of individual mPTP components cannot explain the intrinsic differences in the sensitivity to Ca 2+ -induced mPT seen in isolated mitochondria from spinal cord and brain [83,84]. Not all mitochondria within individual motor neurons contain CyPD, ANT, and VDAC [81]; this observation supports the idea that mitochondria in individual cells are not only heterogeneous in shape [85,86] but also in biochemical composition, metabolism [87] and genetics [8]. …”

Section: Types Of Cell Deathmentioning

confidence: 86%

Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases

2010

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Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy.

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Comparative Studies on Mitochondria Isolated From Neuron-Enriched and Glia-Enriched Fractions of Rabbit and Beef Brain

Cited by 114 publications

References 29 publications

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

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

The mitochondrial permeability transition pore: A molecular target for amyotrophic lateral sclerosis therapy

Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases

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