Volume 18, No 12, Dec 2008

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 18 Issue 12, December 2008: 1210-1219

ORIGINAL ARTICLES

Apaf-1-deficient fog mouse cell apoptosis involves hypo-polarization of the mitochondrial inner membrane, ATP depletion and citrate accumulation

Iyoko Katoh¹, Shingo Sato², Nahoko Fukunishi³, Hiroki Yoshida⁴, Takasuke Imai⁵ and Shun-ichi Kurata³

¹Department of Microbiology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan;
²Department of Immunoregulation, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku 113-8510, Japan;
³Redox Response Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku 113-8510, Japan;
⁴Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8581, Japan;
⁵Department of Critical Care Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku 113-8510, Japan Correspondence: Shun-ichi Kurata(kushbgen@mri.tmd.ac.jp )

To explore how the intrinsic apoptosis pathway is controlled in the spontaneous fog (forebrain overgrowth) mutant mice with an Apaf1 splicing deficiency, we examined spleen and bone marrow cells from Apaf1^+/+ (+/+) and Apaf1^fog/fog (fog/fog) mice for initiator caspase-9 activation by cellular stresses. When the mitochondrial inner membrane potential (Δψm) was disrupted by staurosporine, +/+ cells but not fog/fog cells activated caspase-9 to cause apoptosis, indicating the lack of apoptosome (apoptosis protease activating factor 1 (Apaf-1)/cytochrome c/(d)ATP/procaspase-9) function in fog/fog cells. However, when a marginal (~20%) decrease in Δψm was caused by hydrogen peroxide (0.1 mM), peroxynitritedonor 3-morpholinosydnonimine (0.1 mM) and UV-C irradiation (20 J/m²), both +/+ and fog/fog cells triggered procaspase-9 auto-processing and its downstream cascade activation. Supporting our previous results, procaspase-9 pre-existing in the mitochondria induced its auto-processing before the cytosolic caspase activation regardless of the genotypes. Cellular ATP concentration significantly decreased under the hypoactive Δψm condition. Furthermore, we detected accumulation of citrate, a kosmotrope known to facilitate procaspase-9 dimerization, probably due to a feedback control of the Krebs cycle by the electron transfer system. Thus, mitochondrial in situ caspase-9 activation may be caused by the major metabolic reactions in response to physiological stresses, which may represent a mode of Apaf-1-independent apoptosis hypothesized from recent genetic studies.

Cell Research (2008) 18:1210-1219. doi: 10.1038/cr.2008.87; published online 29 July 2008

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