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. 2015 Jul 31;117(4):346-51.
doi: 10.1161/CIRCRESAHA.117.306859. Epub 2015 Jun 2.

Interdependence of Parkin-Mediated Mitophagy and Mitochondrial Fission in Adult Mouse Hearts

Moshi Song  1 , Guohua Gong  1 , Yan Burelle  1 , Åsa B Gustafsson  1 , Richard N Kitsis  1 , Scot J Matkovich  1 , Gerald W Dorn 2nd  2
Affiliations

Interdependence of Parkin-Mediated Mitophagy and Mitochondrial Fission in Adult Mouse Hearts

Moshi Song et al. Circ Res. .

Abstract

Rationale: The role of Parkin in hearts is unclear. Germ-line Parkin knockout mice have normal hearts, but Parkin is protective in cardiac ischemia. Parkin-mediated mitophagy is reportedly either irrelevant, or a major factor, in the lethal cardiomyopathy evoked by cardiac myocyte-specific interruption of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission.

Objective: To understand the role of Parkin-mediated mitophagy in normal and mitochondrial fission-defective adult mouse hearts.

Methods and results: Parkin mRNA and protein were present at low levels in normal mouse hearts, but were upregulated after cardiac myocyte-directed Drp1 gene deletion in adult mice. Alone, forced cardiac myocyte Parkin overexpression activated mitophagy without adverse effects. Likewise, cardiac myocyte-specific Parkin deletion evoked no adult cardiac phenotype, revealing no essential function for, and tolerance of, Parkin-mediated mitophagy in normal hearts. Concomitant conditional Parkin deletion with Drp1 ablation in adult mouse hearts prevented Parkin upregulation in mitochondria of fission-defective hearts, also increasing 6-week survival, improving ventricular ejection performance, mitigating adverse cardiac remodeling, and decreasing cardiac myocyte necrosis and replacement fibrosis. Underlying the Parkin knockout rescue was suppression of Drp1-induced hyper-mitophagy, assessed as ubiquitination of mitochondrial proteins and mitochondrial association of autophagosomal p62/sequestosome 1 (SQSTM1) and processed microtubule-associated protein 1 light chain 3 (LC3-II). Consequently, mitochondrial content of Drp1-deficient hearts was preserved. Parkin deletion did not alter characteristic mitochondrial enlargement of Drp1-deficient cardiac myocytes.

Conclusions: Parkin is rare in normal hearts and dispensable for constitutive mitophagic quality control. Ablating Drp1 in adult mouse cardiac myocytes not only interrupts mitochondrial fission, but also markedly upregulates Parkin, thus provoking mitophagic mitochondrial depletion that contributes to the lethal cardiomyopathy.

Keywords: Parkin protein; cardiomyopathies; mice; mitochondria; mitochondrial degradation; mitochondrial dynamics.

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Figures

Figure 1
Figure 1. Parkin expression in normal and Drp1-deficient hearts
A. RNA Sequencing of Parkin (Park2) and related factors in 25 normal adult mouse hearts. B. RT-qPCR of Parkin mRNA expression in normal, cardiac Parkin knockout (KO), and cardiac Drp1 KO hearts. C. Immunoblot analysis of myocardial Parkin after conditional cardiac myocyte-directed Drp1 ablation; each lane is a different mouse heart.
Figure 2
Figure 2. Cardiac Parkin overexpression
A. Immunoblot analyses of Parkin and mitophagy markers in mitochondria-enriched (10,000 ×g pellet; mito-) and -depleted (10,000 ×g supernatant) cardiac fractions; parallel blots were run and probed simultaneously. B–C. Cardiac phenotyping in 30 week old Parkin transgenic (TG) mice: B. Representative hearts, echocardiograms, and Masson’s trichrome histology; bar scale is 50 µm. C. Quantitative data. D. Isolated mitochondrial respiration. E. Mitochondrial abundance and flow cytometry studies. Grey curve is representative Ctrl; black is cardiac Parkin transgenic.
Figure 3
Figure 3. Cardiac myocyte-specific Parkin ablation
A. Schematic of ablation strategy; inset shows PCR demonstrating Cre-mediated Park2 gene recombination. B–C. Cardiac phenotyping in 28 week old mice: B. Representative hearts, echocardiograms, and Masson’s trichrome histology; bar scale is 50 µm. C. Quantitative data. D. Isolated mitochondrial respiration. E. Mitochondrial abundance and flow cytometry studies. Grey curve is representative Ctrl; black is cardiac Parkin KO.
Figure 4
Figure 4. Parkin deficiency delays cardiomyopathy and mitigates mitophagy in Drp1 deficiency
A. Schematic depiction of combined conditional cardiac Drp1/Parkin deletion strategy; inset shows normalization of Parkin levels in combined KO hearts. B. Representative hearts and M-mode echocardiograms 6 weeks after gene ablation. C. Time-dependent change in LV fractional shortening; dead mouse icon indicates LV FS data for ~50% surviving cardiac Drp1 KO mice at 6 wks. D. Masson’s trichrome (top) and in vivo Evan’s blue (bottom) stained cardiac sections; quantitative data to the right. E. Immunoblotting of mitophagy factors in mitochondrial fractions; quantitative data to the right; each lane is a different mouse heart. F. Representative transmission electron microscopy (EM). Quantitative metrics for mitochondria are to the right. *P<0.05 versus identically treated controls; #P<0.05 versus Drp1 KO.
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Comment in

  • Parkin Gone Wild: Unbridled Ubiquitination.
    Cao DJ, Lavandero S, Hill JA. Cao DJ, et al. Circ Res. 2015 Jul 31;117(4):311-3. doi: 10.1161/CIRCRESAHA.115.307022. Circ Res. 2015. PMID: 26227875 Free PMC article. No abstract available.

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