Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury

Abstract

Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantity in vivo. Hypoxia induced extensive mitochondrial degradation in a FUNDC1-dependent manner in platelets, and this was blocked by in vivo administration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice. Genetic ablation of Fundc1 impaired mitochondrial quality and increased mitochondrial mass in platelets and rendered the platelets insensitive to hypoxia and the peptide. Moreover, hypoxic mitophagy in platelets protected the heart from worsening of I/R injury. This represents a new mechanism of the hypoxic preconditioning effect which reduces I/R injury. Our results demonstrate a critical role of mitophagy in mitochondrial quality control and platelet activation, and suggest that manipulation of mitophagy by hypoxia or pharmacological approaches may be a novel strategy for cardioprotection.DOI: http://dx.doi.org/10.7554/eLife.21407.001

FUN14 Domain‐Containing 1–Mediated Mitophagy Suppresses Hepatocarcinogenesis by Inhibition of Inflammasome Activation in Mice

“…All experimental mice were of C57BL/6 genetic background and maintained in the same conditions. FUNDC1 whole‐body knockout mice were generated as described …”

“…FUNDC1 whole-body knockout mice were generated as described. (29) Albulin-Cre mice were crossed with FUNDC1 fl/fl to generate the hepatocyte-specific knockout mice (FUNDC1 Δhep ). To confirm FUNDC1 deletion in hepatocytes, tail genomic DNA was extracted and genotyping was done by PCR analysis using the following primers: F: 5′-GGAACAG CTCCAGATGGCAA-3′; R: 5′-AGCATGTTTAG CTGGCCCAA-3′.…”

Mitochondrial quality control in cardiac cells: Mechanisms and role in cardiac cell injury and disease

“…Mitophagy improves energy metabolism of platelets, therefore, activated platelets form thrombi and occlude the coronary artery leading to secondary ischemia and contribute to cardiac IR injury (Zhang et al, b). In this regard, pharmacological or genetic manipulation of FUNDC1‐mediated mitophagy in platelets, which suppresses their hyperactivity, can protect the heart against IR injury (Zhang et al, , Zhang et al, ; Zhou et al, c).…”

Mitophagy imbalance in cardiomyocyte ischaemia/reperfusion injury

“…76,97 Phosphorylation of FUNDC1 Ser17 by ULK1 or dephosphorylation of FUNDC1 Ser13 by PGAM 5 can promote the interaction between FUNDC1 and LC3B, whereas the phosphorylation of FUNDC1 Ser13 by CK2α or the phosphorylation of FUNDC1 Tyr18 by Src or Ripk3 can decrease the binding affinities for LC3B. [97][98][99][100] It is demonstrated that the phosphorylation status of FUNDC1 Tyr18 and Ser13 participates in regulating the binding affinities of FUNDC1 and mitophagy in cardiomyocytes upon I/R. I/R increases FUNDC1 Tyr18 phosphorylation by up-regulation of Ripk3 expression and FUNDC1 Ser13 phosphorylation by up-regulation of CK2 α to inactivate FUNDC1, thus inhibiting mitophagy.…”

“…And it has been proved that membrane-penetrating peptides targeting mitophagy in platelets have strong cardioprotective effects against I/R injury in mice. 100,101 The peptide approach might hold promise for future therapeutic applications.…”