McLaughlin 2018 Biochem Biophys Res Commun

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McLaughlin KL, McClung JM, Fisher-Wellman KH (2018) Bioenergetic consequences of compromised mitochondrial DNA repair in the mouse heart. Biochem Biophys Res Commun 504:742-48.

» PMID: 30217445

McLaughlin KL, McClung JM, Fisher-Wellman KH (2018) Biochem Biophys Res Commun

Abstract: The progeroid phenotype of mitochondrial DNA (mtDNA) mutator mice has been nebulously attributed to general mitochondrial 'dysfunction', though few studies have rigorously defined the bioenergetic consequences of accumulating mtDNA mutations. Comprehensive mitochondrial diagnostics was employed to interrogate the bioenergetic properties of isolated cardiac mitochondria from mtDNA mutator mice and wild type littermates. Assessment of respiratory flux in conjunction with parallel measurements of mitochondrial free energy all point to the cause of respiratory flux limitations observed in mtDNA mutator mouse mitochondria being due to impairments within the energy transduction step catalyzed by the electron transport system in which NADH/NAD+ free energy is transduced to the proton motive force (ΔP). The primary bioenergetic consequence of this limitation appears to be hyper-reduction of NAD(P)H/NAD(P)+ redox poise across multiple substrate conditions, particularly evident at moderate to high respiration rates. This hyper-reduced phenotype appears to result from specific reductions in both complex I and complex IV expression, presumably due to compromised mtDNA integrity. Translation of these findings to the working heart would suggest that the primary biological consequence of accumulated mtDNA damage is accelerated electron leak driven by an increase in electron redox pressure for a given rate of oxygen consumption.

Copyright © 2018 Elsevier Inc. All rights reserved.

Keywords: Bioenergetics, DNA polymerase gamma, Heart, Mitochondrial DNA, Reactive oxygen species Bioblast editor: Plangger M


Labels: MiParea: Respiration, mtDNA;mt-genetics 


Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase  Regulation: mt-Membrane potential, PCr;Cr 

Pathway: F, N, S  HRR: Oxygraph-2k 

Labels, 2019-01