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Mol Neurobiol. 2019 May;56(5):3722-3735. doi: 10.1007/s12035-018-1335-y. Epub 2018 Sep 6.

Ablation of Cytochrome c in Adult Forebrain Neurons Impairs Oxidative Phosphorylation Without Detectable Apoptosis.

Author information

1
Department of Neurology, Miller School of Medicine Miami, University of Miami, 1420 NW 9th Avenue, TSL Building, Rm. 231, Miami, FL, 33136, USA. mpinto@med.miami.edu.
2
Department of Neurology, Miller School of Medicine Miami, University of Miami, 1420 NW 9th Avenue, TSL Building, Rm. 231, Miami, FL, 33136, USA.
3
Neuroscience Program, Miller School of Medicine Miami, University of Miami, 1420 NW 9th Avenue, TSL Building, Rm. 231, Miami, FL, 33136, USA.
4
Department of Neurology, Miller School of Medicine Miami, University of Miami, 1420 NW 9th Avenue, TSL Building, Rm. 231, Miami, FL, 33136, USA. cmoraes@med.miami.edu.
5
Neuroscience Program, Miller School of Medicine Miami, University of Miami, 1420 NW 9th Avenue, TSL Building, Rm. 231, Miami, FL, 33136, USA. cmoraes@med.miami.edu.

Abstract

Cytochrome c (Cyt c), a heme-containing mitochondrial protein, has a critical function in both respiration and apoptosis. Consistent with these vital functions, somatic Cyt c mouse knockout is embryonic lethal. In order to investigate the sensitivity of postnatal neurons to Cyt c depletion, we developed a neuron-specific conditional knockout model. Neuron-specific Cyt c KO mouse (nCytcKO) was created by crossing the floxed Cyt c mouse with a CamKIIα-cre transgenic mouse, which deletes the floxed alleles postnatally. nCytcKO mice were normal at birth but developed an abnormal phenotype starting at 8 weeks of age with weight loss, tremor, decreased sensorimotor coordination, and sudden death between 12 and 16 weeks. Histological analysis did not show major neuronal degeneration. Analyses of oxidative phosphorylation showed a specific reduction in complex IV levels. Markers of oxidative stress were also increased. This novel model showed that neuronal complex IV is destabilized in the absence of Cyt c. It also showed that ablation of Cyt c in neurons leads to severe behavioral abnormalities and premature death without detectable neuronal loss, suggesting that neurons have the potential to survive for extended periods of time without a functional OXPHOS.

KEYWORDS:

Conditional knock out; Cytochrome c; Mitochondrial dysfunction

PMID:
30191381
DOI:
10.1007/s12035-018-1335-y
[Indexed for MEDLINE]

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