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Mitochondrial dynamism and heart disease: changing shape and shaping change.

Dorn GW - EMBO Mol Med (2015)

Bottom Line: Nevertheless, proteins essential to mitochondrial network remodeling are abundant in adult hearts.Recent findings from cardiac-specific ablation of mitochondrial fission and fusion protein genes have revealed unexpected roles for mitochondrial dynamics factors in mitophagic mitochondrial quality control.This overview examines the clinical and experimental evidence for and against a meaningful role for the mitochondrial dynamism-quality control interactome in normal and diseased hearts.

View Article: PubMed Central - PubMed

Affiliation: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA gdorn@dom.wustl.edu.

No MeSH data available.


Related in: MedlinePlus

Asymmetric fission for mitochondrial quality controlA damaged or senescent mitochondrion (mixture of damaged yellow/orange and healthy green components) is shown. Via asymmetric fission, the healthy components are delivered to one daughter that is fusion-competent, rejuvenated, and retained. The damaged components are segregated into the other, smaller daughter that is depolarized and promptly eliminated via mitophagy.
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fig05: Asymmetric fission for mitochondrial quality controlA damaged or senescent mitochondrion (mixture of damaged yellow/orange and healthy green components) is shown. Via asymmetric fission, the healthy components are delivered to one daughter that is fusion-competent, rejuvenated, and retained. The damaged components are segregated into the other, smaller daughter that is depolarized and promptly eliminated via mitophagy.

Mentions: The most straightforward explanation for how defective mitochondrial fusion or fission can adversely impact mitophagy is that an intact fission–fusion cycle is essential for asymmetric mitochondrial fission in which damaged or malfunctioning mitochondrial components are segregated from healthy components and targeted for removal (Twig et al, 2008; Dorn, 2015) (Fig5). However, a fission–fusion cycle defect does not explain why Mfn2 ablation produces greater mitochondrial dysfunction than Mfn1 ablation (see above), or reveal why Parkin translocation defects in neurons and cardiomyocytes are exclusively evoked by Mfn2 deficiency (Lee et al, 2012; Pham et al, 2012; Chen & Dorn, 2013). A molecular mechanism was provided by our observation that Mfn2 is enabled as a mitochondrial-localized binding protein for Parkin after its phosphorylation by the PINK1 kinase (Chen & Dorn, 2013). PINK1 is preferentially stabilized in damaged/depolarized mitochondria, with the consequence that Parkin translocates to that organelle and stimulates its mitophagy by ubiquitinating mitochondrial proteins (see Fig3; Narendra et al, 2010). In our in vivo studies, Mfn2 is an essential intermediate in the interaction between mitochondrial PINK1 and cytosolic Parkin, being phosphorylated by the former and thereby transformed into a mitochondrial binding partner for the latter (Chen & Dorn, 2013). The dual role of Mfn2 as both mitochondrial fusion factor and Parkin receptor in the mitophagy appears sufficient to explain mitochondrial enlargement, degeneration, and proliferation in Mfn2 deficiency in the heart (Dorn & Kitsis, 2015) and brain (Lee et al, 2012).


Mitochondrial dynamism and heart disease: changing shape and shaping change.

Dorn GW - EMBO Mol Med (2015)

Asymmetric fission for mitochondrial quality controlA damaged or senescent mitochondrion (mixture of damaged yellow/orange and healthy green components) is shown. Via asymmetric fission, the healthy components are delivered to one daughter that is fusion-competent, rejuvenated, and retained. The damaged components are segregated into the other, smaller daughter that is depolarized and promptly eliminated via mitophagy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520653&req=5

fig05: Asymmetric fission for mitochondrial quality controlA damaged or senescent mitochondrion (mixture of damaged yellow/orange and healthy green components) is shown. Via asymmetric fission, the healthy components are delivered to one daughter that is fusion-competent, rejuvenated, and retained. The damaged components are segregated into the other, smaller daughter that is depolarized and promptly eliminated via mitophagy.
Mentions: The most straightforward explanation for how defective mitochondrial fusion or fission can adversely impact mitophagy is that an intact fission–fusion cycle is essential for asymmetric mitochondrial fission in which damaged or malfunctioning mitochondrial components are segregated from healthy components and targeted for removal (Twig et al, 2008; Dorn, 2015) (Fig5). However, a fission–fusion cycle defect does not explain why Mfn2 ablation produces greater mitochondrial dysfunction than Mfn1 ablation (see above), or reveal why Parkin translocation defects in neurons and cardiomyocytes are exclusively evoked by Mfn2 deficiency (Lee et al, 2012; Pham et al, 2012; Chen & Dorn, 2013). A molecular mechanism was provided by our observation that Mfn2 is enabled as a mitochondrial-localized binding protein for Parkin after its phosphorylation by the PINK1 kinase (Chen & Dorn, 2013). PINK1 is preferentially stabilized in damaged/depolarized mitochondria, with the consequence that Parkin translocates to that organelle and stimulates its mitophagy by ubiquitinating mitochondrial proteins (see Fig3; Narendra et al, 2010). In our in vivo studies, Mfn2 is an essential intermediate in the interaction between mitochondrial PINK1 and cytosolic Parkin, being phosphorylated by the former and thereby transformed into a mitochondrial binding partner for the latter (Chen & Dorn, 2013). The dual role of Mfn2 as both mitochondrial fusion factor and Parkin receptor in the mitophagy appears sufficient to explain mitochondrial enlargement, degeneration, and proliferation in Mfn2 deficiency in the heart (Dorn & Kitsis, 2015) and brain (Lee et al, 2012).

Bottom Line: Nevertheless, proteins essential to mitochondrial network remodeling are abundant in adult hearts.Recent findings from cardiac-specific ablation of mitochondrial fission and fusion protein genes have revealed unexpected roles for mitochondrial dynamics factors in mitophagic mitochondrial quality control.This overview examines the clinical and experimental evidence for and against a meaningful role for the mitochondrial dynamism-quality control interactome in normal and diseased hearts.

View Article: PubMed Central - PubMed

Affiliation: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA gdorn@dom.wustl.edu.

No MeSH data available.


Related in: MedlinePlus