Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice

Gong, Guohua; Song, Moshi; Csordás, György; Kelly, Daniel P.; Matkovich, Scot J.; Dorn, Gerald W.

doi:10.1126/science.aad2459

Cited by 372 publications

(400 citation statements)

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“…elimination of dysfunctional mitochondria but mitochondrial turnover for metabolic transitioning from carbohydrates to fatty acids in cardiomyocytes during the perinatal period [13]. This observation is similar to the role of Nix-mediated mitophagy in the terminal stages of normal erythrocyte development [14].…”

Section: Accepted M Manuscriptsupporting

confidence: 64%

Receptor-mediated mitophagy

Yamaguchi

Murakawa

Nishida

et al. 2016

Journal of Molecular and Cellular Cardiology

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Section: Accepted M Manuscriptsupporting

confidence: 64%

Receptor-mediated mitophagy

Yamaguchi

Murakawa

Nishida

et al. 2016

Journal of Molecular and Cellular Cardiology

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“…Specifically, MFN2AA mice develop cardiomyopathy and die prematurely by 8 weeks of age (80). Interestingly, the resultant cardiac mitochondria maintain a fetal phenotype similar to that seen with PGC-1α/β deficiency (80). In turn, postnatal induction of ERR and PPARα target gene expression is also blocked in these mice.…”

Section: Control Of Cardiac Mitochondrial Biogenesis and Dynamics: Thmentioning

confidence: 96%

“…Therefore, inhibition of Parkin-MFN2 docking or MFN2 phosphorylation will block mitophagy. Indeed, cardiac expression of a non-phosphorylatable MFN2 mutant (MFN2AA) prevents mitochondrial recruitment of Parkin and results in reduced mitochondrial respiratory capacity and ultrastructural mitochondrial defects in mice (80). Specifically, MFN2AA mice develop cardiomyopathy and die prematurely by 8 weeks of age (80).…”

Section: Control Of Cardiac Mitochondrial Biogenesis and Dynamics: Thmentioning

confidence: 99%

“…Indeed, cardiac expression of a non-phosphorylatable MFN2 mutant (MFN2AA) prevents mitochondrial recruitment of Parkin and results in reduced mitochondrial respiratory capacity and ultrastructural mitochondrial defects in mice (80). Specifically, MFN2AA mice develop cardiomyopathy and die prematurely by 8 weeks of age (80). Interestingly, the resultant cardiac mitochondria maintain a fetal phenotype similar to that seen with PGC-1α/β deficiency (80).…”

Section: Control Of Cardiac Mitochondrial Biogenesis and Dynamics: Thmentioning

confidence: 99%

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Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

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“…Disruption of mitochondrial function causes an accumulation of PINK1 on the mitochondrial outer membrane where it phosphorylates ubiquitin and Parkin leading to activation of the PARKIN E3 ubiquitin ligase at the mitochondria [9][10][11] . Parkin recruitment to mitochondria requires mitofusin 2 (MFN2) in some settings 12,13 but is dispensible in others 14 . In a feed-forward mechanism, Parkin ubiquitinates mitochondrial substrates that, in turn, leads to more PINK1 substrate phosphorylation and Parkin activity.…”

Section: Introductionmentioning

confidence: 99%

Depletion of mitochondria in mammalian cells through enforced mitophagy

et al. 2016

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Mitochondria are not only the "power-house" of the cell, but are also involved in a multitude of processes that include calcium storage, cell-cycle and cell-death. Traditional means to investigate mitochondrial importance in a given cellular process have centred upon depletion of mitochondrial DNA (mtDNA) through chemical or genetic means. While these methods severely disrupt mitochondrial electron transport chain, mtDNA-depleted cells still maintain mitochondria and many mitochondrial functions. Here, we describe a straightforward protocol to generate mammalian cell populations with low to non-detectable levels of mitochondria. Ectopic expression of the ubiquitin E3 ligase Parkin, combined with short-term mitochondrial uncoupler treatment, engages widespread mitophagy, and effectively eliminates mitochondria. In this protocol, we explain how to generate mitochondria-depleted cells and a variety of methods to confirm mitochondrial clearance. Furthermore, we describe culture conditions to maintain mitochondrial-depleted cells with minimal loss of viability for longitudinal studies. This method should prove useful to investigate the importance of mitochondria in a variety of biological processes.

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Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice

Cited by 372 publications

References 50 publications

Receptor-mediated mitophagy

Receptor-mediated mitophagy

Cardiac nuclear receptors: architects of mitochondrial structure and function

Depletion of mitochondria in mammalian cells through enforced mitophagy

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