Mice deficient in dihydrolipoyl succinyl transferase show increased vulnerability to mitochondrial toxins

Lichuan Yang; Qingli Shi; Daniel J. Ho; Anatoly A. Starkov; Elizabeth J. Wille; Hui Xu; H.L. Chen; Steven Zhang; Cliona M. Stack; Noel Y. Calingasan; Gary E. Gibson; M. Flint Beal

Neurobiology of Disease (Nov 2009)

Mice deficient in dihydrolipoyl succinyl transferase show increased vulnerability to mitochondrial toxins

Lichuan Yang,
Qingli Shi,
Daniel J. Ho,
Anatoly A. Starkov,
Elizabeth J. Wille,
Hui Xu,
H.L. Chen,
Steven Zhang,
Cliona M. Stack,
Noel Y. Calingasan,
Gary E. Gibson,
M. Flint Beal

Affiliations

Lichuan Yang: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA
Qingli Shi: Department of Neurology and Neuroscience, Weill Cornell Medical College at Burke Medical Research Institute, White Plains, NY 10605, USA
Daniel J. Ho: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA
Anatoly A. Starkov: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA
Elizabeth J. Wille: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA
Hui Xu: Department of Neurology and Neuroscience, Weill Cornell Medical College at Burke Medical Research Institute, White Plains, NY 10605, USA
H.L. Chen: Department of Neurology and Neuroscience, Weill Cornell Medical College at Burke Medical Research Institute, White Plains, NY 10605, USA
Steven Zhang: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA
Cliona M. Stack: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA
Noel Y. Calingasan: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA
Gary E. Gibson: Department of Neurology and Neuroscience, Weill Cornell Medical College at Burke Medical Research Institute, White Plains, NY 10605, USA; Corresponding authors. G.E. Gibson is to be contacted at the Department of Neurology and Neuroscience, Weill Cornell Medical College at Burke Medical Research Institute, White Plains, NY 10605, USA. M. Flint Beal, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York Presbyterian Hospital, 525 East 68th Street, F610, New York, NY 10021, USA.
M. Flint Beal: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA; Corresponding authors. G.E. Gibson is to be contacted at the Department of Neurology and Neuroscience, Weill Cornell Medical College at Burke Medical Research Institute, White Plains, NY 10605, USA. M. Flint Beal, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York Presbyterian Hospital, 525 East 68th Street, F610, New York, NY 10021, USA.

Journal volume & issue: Vol. 36, no. 2
pp. 320 – 330

Abstract

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The activity of a key mitochondrial tricarboxylic acid cycle enzyme, α-ketoglutarate dehydrogenase complex (KGDHC), declines in many neurodegenerative diseases. KGDHC consists of three subunits. The dihydrolipoyl succinyl transferase (DLST) component is unique to KGDHC. DLST+/− mice showed reduced mRNA and protein levels and decreased brain mitochondrial KGDHC activity. Neurotoxic effects of mitochondrial toxins were exacerbated in DLST+/− mice. MPTP produced a significantly greater reduction of striatal dopamine and tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta of DLST+/− mice. DLST deficiency enhanced the severity of lipid peroxidation in the substantia nigra after MPTP treatment. Striatal lesions induced by either malonate or 3-nitropropionic acid (3-NP) were significantly larger in DLST+/− mice than in wildtype controls. DLST deficiency enhanced the 3-NP inhibition of mitochondria enzymes, and 3-NP induced protein and DNA oxidations. These observations support the hypothesis that reductions in KGDHC may impair the adaptability of the brain and contribute to the pathogenesis of neurodegenerative diseases.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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