The role of MTP18 in mitochondrial dynamics and metabolism

Identification: Patitucci, Cecilia


Description

The role of MTP18 in mitochondrial dynamics and metabolism
 
Patitucci C.1, Donnarumma E.1, Ryan M. 2, Wai T.1
1Insitut Necker Enfants Malades, Inserm U1151/CNRS UMR 8253 Faculté de Médecine Université de Paris Descartes, Paris, France; 2Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia.
 
The essential machinery of outer membrane fusion and fission is well established but less is known about the mechanisms of inner membrane dynamics. With the aim of understanding inner membrane fission, we have focused on Mitochondrial protein of 18 kDa (MTP18), which is the only inner membrane protein to our knowledge that exhibits features of a fission factor. We aim to investigate the role of MTP18 in the control of mitochondrial morphology and function and its relevance in vivo.
We generated cell and mouse models to perform gain-of-function and loss-of-function experiments in order to gain insights into the function of this protein. Consistent with its pro-fission role, overexpression of MTP18 in cultured cells induces Drp1 recruitment on the mitochondrial surface and increases mitochondria fragmentation. Overexpression of MTP18 in vitro and in vivo does not affect the levels of known components of the fusion and fission apparatus. Mice subjected to acute hepatic MTP18 overexpression using AAV8 vectors showed no signs of inflammation or fibrosis in the liver. In vitro, MTP18-mediated mitochondrial fragmentation depends on Drp1 and its receptors. Overexpression of MTP18 does not induce fragmentation in cultured cells lacking DRP1 or the receptors Mff, Mid49 and Mid51. Moreover, the overexpression of MTP18 does not cause stress-induced OPA1 processing, suggesting that MTP18 is downstream of OMA1 activation.
To study the physiological relevance of MTP18, we generated whole-body MTP18 KO mice (MKO) by crossing conditional MTP18LoxP/LoxP mice to Cmv-Cre recombinase mice followed by heterozygous intercrossing on a C57BL/6N background. Unlike DRP1 KO mice, MTP18 whole body deletion did not lead to embryonic lethality. At 4-months old, MKO mice appear no different from wild-type littermates and exhibited normal body mass and fat/lean mass composition. Nevertheless, MKO mice showed reduced oxygen consumption rates in isolated liver mitochondria. Cultured cells deleted for MTP18 by Crispr/Cas9 genome editing approaches recapitulated the bioenergetic defects observed in vivo. Altogether, our data implicate the inner membrane protein MTP18 in the maintenance of normal mitochondrial morphology and energy metabolism.
 

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