An analysis of the effects of Mn{sup 2+} on oxidative phosphorylation in liver, brain, and heart mitochondria using state 3 oxidation rate assays

Journal Article · Sun Nov 14 23:00:00 EST 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.08.018· OSTI ID:21460239

Gerstner, Brent ^[1]; Lester, Tobias ^[1]; Malecki, Jon ^[1]

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1. Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642 (United States)

Manganese (Mn) toxicity is partially mediated by reduced ATP production. We have used oxidation rate assays-a measure of ATP production-under rapid phosphorylation conditions to explore sites of Mn{sup 2+} inhibition of ATP production in isolated liver, brain, and heart mitochondria. This approach has several advantages. First, the target tissue for Mn toxicity in the basal ganglia is energetically active and should be studied under rapid phosphorylation conditions. Second, Mn may inhibit metabolic steps which do not affect ATP production rate. This approach allows identification of inhibitions that decrease this rate. Third, mitochondria from different tissues contain different amounts of the components of the metabolic pathways potentially resulting in different patterns of ATP inhibition. Our results indicate that Mn{sup 2+} inhibits ATP production with very different patterns in liver, brain, and heart mitochondria. The primary Mn{sup 2+} inhibition site in liver and heart mitochondria, but not in brain mitochondria, is the F{sub 1}F{sub 0} ATP synthase. In mitochondria fueled by either succinate or glutamate + malate, ATP production is much more strongly inhibited in brain than in liver or heart mitochondria; moreover, Mn{sup 2+} inhibits two independent sites in brain mitochondria. The primary site of Mn-induced inhibition of ATP production in brain mitochondria when succinate is substrate is either fumarase or complex II, while the likely site of the primary inhibition when glutamate plus malate are the substrates is either the glutamate/aspartate exchanger or aspartate aminotransferase.

• OSTI ID: 21460239
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 249; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ATP
BODY
BRAIN
CARDIOVASCULAR SYSTEM
CELL CONSTITUENTS
CENTRAL NERVOUS SYSTEM
CHARGED PARTICLES
CHEMICAL REACTIONS
DIGESTIVE SYSTEM
GLANDS
HEART
IONS
LIVER
MANGANESE IONS
MITOCHONDRIA
NERVOUS SYSTEM
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANS
OXIDATION
PHOSPHORYLATION
TOXICITY