Interdependence of parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts

Moshi Song, Guohua Gong, Yan Burelle, Åsa B. Gustafsson, Richard N. Kitsis, Scot J. Matkovich, Gerald W. Dorn

Research output: Contribution to journalArticle

67 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)346-351
Number of pages6
JournalCirculation Research
Volume117
Issue number4
DOIs
StatePublished - Jul 1 2015

Fingerprint

Mitochondrial Degradation
Mitochondrial Dynamics
Dynamins
Cardiac Myocytes
Proteins
Cardiomyopathies
Up-Regulation
Microtubule-Associated Proteins
Ubiquitination
Mitochondrial Proteins
Gene Deletion
Knockout Mice
Germ Cells
Quality Control
Mitochondria
Fibrosis
Necrosis
Ischemia

Keywords

  • Cardiomyopathies
  • Mice
  • Mitochondria
  • Mitochondrial degradation
  • Mitochondrial dynamics
  • Parkin protein

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Interdependence of parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts. / Song, Moshi; Gong, Guohua; Burelle, Yan; Gustafsson, Åsa B.; Kitsis, Richard N.; Matkovich, Scot J.; Dorn, Gerald W.

In: Circulation Research, Vol. 117, No. 4, 01.07.2015, p. 346-351.

Research output: Contribution to journalArticle

Song, M, Gong, G, Burelle, Y, Gustafsson, ÅB, Kitsis, RN, Matkovich, SJ & Dorn, GW 2015, 'Interdependence of parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts', Circulation Research, vol. 117, no. 4, pp. 346-351. https://doi.org/10.1161/CIRCRESAHA.117.306859
Song, Moshi ; Gong, Guohua ; Burelle, Yan ; Gustafsson, Åsa B. ; Kitsis, Richard N. ; Matkovich, Scot J. ; Dorn, Gerald W. / Interdependence of parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts. In: Circulation Research. 2015 ; Vol. 117, No. 4. pp. 346-351.
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AU - Gustafsson, Åsa B.

AU - Kitsis, Richard N.

AU - Matkovich, Scot J.

AU - Dorn, Gerald W.

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KW - Mitochondrial degradation

KW - Mitochondrial dynamics

KW - Parkin protein

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