Cardiolipin is essential for early embryonic viability and mitochondrial integrity of neurons in mammals. Issue 1 (2nd December 2019)

• Record Type: Journal Article
• Authors: Kasahara, Takaoki; Kubota‐Sakashita, Mie; Nagatsuka, Yasuko; Hirabayashi, Yoshio; Hanasaka, Tomohito; Tohyama, Koujiro; Kato, Tadafumi
• Is Part Of: FASEB journal. Volume 34:Issue 1(2020)
• Page Start: 1465
• Page End: 1480
• Publication Date: 2019-12-02
• Subjects: Crls1 -- mitochondrial cristae -- calcium retention capacity -- peri‐implantation lethality -- Camk2α‐Cre mice; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201901598R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: Cardiolipin (CL) is a hallmark phospholipid of mitochondria and plays a significant role in maintaining the mitochondrial structure and functions. Despite the physiological importance of CL, mutant organisms, yeast, Arabidopsis, C elegans, and Drosophila, which lack CL synthase ( Crls1 ) gene and consequently are deprived of CL, are viable. Here we report conditional Crls1 ‐deficient mice using targeted insertion of loxP sequences flanking the functional domain of CRLS1 enzyme. Homozygous null mutant mice exhibited early embryonic lethality at the peri‐implantation stage. We generated neuron‐specific Crls1 knockout (cKO) mice by crossing with Camk2α‐Cre mice. Neuronal loss and gliosis were gradually manifested in the forebrains, where CL levels were significantly decreased. In the surviving neurons, malformed mitochondria with bubble‐like or onion‐like inner membrane structures were observed. We showed decreased supercomplex assembly and reduced enzymatic activities of electron transport chain complexes in the forebrain of cKO mice, resulting in affected mitochondrial calcium dynamics, a slower rate of Ca 2+ uptake and a smaller calcium retention capacity. These observations clearly demonstrate indispensable roles of CL as well as of Crls1 gene in mammals.