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Parkin does not prevent accelerated cardiac aging in mitochondrial DNA mutator mice
Benjamin P. Woodall, … , Anne N. Murphy, Åsa B. Gustafsson
Benjamin P. Woodall, … , Anne N. Murphy, Åsa B. Gustafsson
Published April 16, 2019
Citation Information: JCI Insight. 2019;4(10):e127713. https://doi.org/10.1172/jci.insight.127713.
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Research Article Cardiology Cell biology

Parkin does not prevent accelerated cardiac aging in mitochondrial DNA mutator mice

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Abstract

The E3 ubiquitin ligase Parkin plays an important role in regulating clearance of dysfunctional or unwanted mitochondria in tissues, including the heart. However, whether Parkin also functions to prevent cardiac aging by maintaining a healthy population of mitochondria is still unclear. Here, we have examined the role of Parkin in the context of mitochondrial DNA (mtDNA) damage and myocardial aging using a mouse model carrying a proofreading-defective mtDNA polymerase γ (POLG). We observed both decreased Parkin protein levels and development of cardiac hypertrophy in POLG hearts with age; however, cardiac hypertrophy in POLG mice was neither rescued, nor worsened by cardiac-specific overexpression or global deletion of Parkin, respectively. Unexpectedly, mitochondrial fitness did not substantially decline with age in POLG mice when compared with that in WT mice. We found that baseline mitophagy receptor–mediated mitochondrial turnover and biogenesis were enhanced in aged POLG hearts. We also observed the presence of megamitochondria in aged POLG hearts. Thus, these processes may limit the accumulation of dysfunctional mitochondria as well as the degree of cardiac functional impairment in the aging POLG heart. Overall, our results demonstrate that Parkin is dispensable for constitutive mitochondrial quality control in a mtDNA mutation model of cardiac aging.

Authors

Benjamin P. Woodall, Amabel M. Orogo, Rita H. Najor, Melissa Q. Cortez, Eileen R. Moreno, Hongxia Wang, Ajit S. Divakaruni, Anne N. Murphy, Åsa B. Gustafsson

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Figure 1

Characterization of cardiac and mitochondrial functions in WT and POLG mice at 6 months of age.

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Characterization of cardiac and mitochondrial functions in WT and POLG m...
(A) Heart weight/body weight (HW/BW) ratios of WT and POLG mice (n = 6–9, ***P < 0.001). Echocardiography showed similar (B) ejection fraction (EF) and fractional shortening (FS) and (C) left ventricular internal dimension at diastole (LVID;d) and systole (LVID;s) in WT and POLG hearts (n = 5–6). Assessment of mitochondrial respiration using isolated mitochondria from WT and POLG hearts show no differences in (D) state 3 respiration (ADP stimulated), (E) state 4 respiration (ADP depleted), (F) respiratory control ratio (RCR), or (G) maximal respiration rates (FCCP uncoupled) with substrates for complex I (pyruvate/malate and palmitoyl carnitine/malate) or II (succinate/rotenone) (n = 10). (H) Representative Western blot of proteins involved in mitochondrial oxidative phosphorylation. (I) Quantitation of proteins (n = 3). COX I, complex I subunit NDUFB8; COX II, complex II subunit 30 kDa; COX III, complex III subunit core 2; COX IV, complex IV subunit II; ATP Synthase, ATP synthase subunit α. Data are mean ± SEM (*P < 0.05). Statistical analysis was performed using Student’s t test.

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