Haploinsufficiency in the mitochondrial protein CHCHD4 reduces brain injury in a mouse model of neonatal hypoxia-ischemia.

Abstract

Mitochondria contribute to neonatal hypoxic-ischemic brain injury by releasing potentially toxic proteins into the cytosol. CHCHD4 is a mitochondrial intermembrane space protein that plays a major role in the import of intermembrane proteins and physically interacts with apoptosis-inducing factor (AIF). The purpose of this study was to investigate the impact of CHCHD4 haploinsufficiency on mitochondrial function and brain injury after cerebral hypoxia-ischemia (HI) in neonatal mice. CHCHD4+/- and wild-type littermate mouse pups were subjected to unilateral cerebral HI on postnatal day 9. CHCHD4 haploinsufficiency reduced insult-related AIF and superoxide dismutase 2 release from the mitochondria and reduced neuronal cell death. The total brain injury volume was reduced by 21.5% at 3 days and by 31.3% at 4 weeks after HI in CHCHD4+/- mice. However, CHCHD4 haploinsufficiency had no influence on mitochondrial biogenesis, fusion, or fission; neural stem cell proliferation; or neural progenitor cell differentiation. There were no significant changes in the expression or distribution of p53 protein or p53 pathway-related genes under physiological conditions or after HI. These results suggest that CHCHD4 haploinsufficiency afforded persistent neuroprotection related to reduced release of mitochondrial intermembrane space proteins. The CHCHD4-dependent import pathway might thus be a potential therapeutic target for preventing or treating neonatal brain injury.

• Authors: Yanyan Sun, Tao Li, Cuicui Xie, Yiran Xu, Kai Zhou, Juan Rodriguez, Wei Han, Xiaoyang Wang, Guido Kroemer, Nazanine Modjtahedi, Klas Blomgren, Changlian Zhu
• Journal: Cell death & disease (Cell Death Dis) Vol. 8 Issue 5 Pg. e2781 (05 11 2017) ISSN: 2041-4889 [Electronic] England
• PMID: 28492551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Inducing Factor
• Mitochondrial Proteins
• AIFM1 protein, mouse
• Superoxide Dismutase
• superoxide dismutase 2

Topics

• Animals
• Apoptosis Inducing Factor (genetics, metabolism)
• Brain Injuries (genetics, metabolism, pathology)
• Brain Ischemia (genetics, metabolism, pathology)
• Disease Models, Animal
• Haploinsufficiency
• Humans
• Mice
• Mitochondrial Proteins (genetics, metabolism)
• Superoxide Dismutase (genetics, metabolism)