Loss of mpv17 affected early embryonic development via mitochondria dysfunction in zebrafish

Abstract

MVP17 encodes a mitochondrial inner-membrane protein, and mutation of human MVP17 can cause mitochondria DNA depletion syndrome (MDDS). However, the underlying function of mpv17 is still elusive. Here, we developed a new mutant with mpv17 knockout by using the CRISPR/Cas9 system. The mpv17−/− zebrafish showed developmental defects in muscles, liver, and energy supply. The mpv17−/− larvae hardly survived beyond a month, and they showed abnormal growth during the development stage. Abnormal swimming ability was also found in the mpv17−/− zebrafish. The transmission electron microscope (TEM) observation indicated that the mpv17−/− zebrafish underwent severe mitochondria dysfunction and the disorder of mitochondrial cristae. As an energy producer, the defects of mitochondria significantly reduced ATP content in mpv17−/− zebrafish, compared to wild-type zebrafish. We hypothesized that the disorder of mitochondria cristae was contributed to the dysfunction of muscle and liver in the mpv17−/− zebrafish. Moreover, the content of major energy depot triglycerides (TAG) was decreased dramatically. Interestingly, after rescued with normal exogenous mitochondria by microinjection, the genes involved in the TAG metabolism pathway were recovered to a normal level. Taken together, this is the first report of developmental defects in muscles, liver, and energy supply via mitochondria dysfunction, and reveals the functional mechanism of mpv17 in zebrafish.

A Drosophila model of the neurological symptoms in Mpv17-related diseases

“…In this study, we demonstrated that CG11077 , an MPV17/PMP22 family gene, is a Drosophila ortholog of mammalian Mpv17 and named it dMpv17 . Human Mpv17 is known as a causal gene of MPV17 -related hepatocerebral MDDS and CMT 4 , 6 , 8 , and models of these diseases have been developed in several organisms such as the mouse and zebrafish 10 , 17 . However, in spite of the fact that most patients show neurological symptoms, neurological defects have not been investigated in these model organisms.…”

“…MPV17 deficiency in mice leads to a reduced deoxynucleotide pool resulting in mtDNA depletion in the liver, but not in the kidney or brain 2 . In zebrafish, diverse phenotypes have been reported in two mpv17 mutants (roy orbison (roy) and transparent (tra)), and Mpv17 KO zebrafish generated by the CRISPR/Cas9 system [13][14][15][16][17] . While roy and tra mutants show only transparent phenotypes with a loss or strong reduction of iridophores and melanophores, Mpv17 KO zebrafish show reduced longevity and defects in muscle, liver, and energy supply during development in addition to a strong reduction of iridophores and melanophores [13][14][15][16][17] .…”

“…In zebrafish, diverse phenotypes have been reported in two mpv17 mutants (roy orbison (roy) and transparent (tra)), and Mpv17 KO zebrafish generated by the CRISPR/Cas9 system [13][14][15][16][17] . While roy and tra mutants show only transparent phenotypes with a loss or strong reduction of iridophores and melanophores, Mpv17 KO zebrafish show reduced longevity and defects in muscle, liver, and energy supply during development in addition to a strong reduction of iridophores and melanophores [13][14][15][16][17] . However, in these studies, the neurological symptoms have not been fully analyzed, albeit human patients with MPV17-related hepatocerebral MDDS commonly show them.…”

The Developmental Progression of Eight Opsin Spectral Signals Recorded from the Zebrafish Retinal Cone Layer Is Altered by the Timing and Cell Type Expression of Thyroxin Receptor β2 (trβ2) Gain-Of-Function Transgenes

“…1 C ). There are several studied mutations of mpv17 all with loss of irridophores ( Bian et al, 2021 ). Here, we use the naturally occurring 19-base-pair intronic deletion of the roy orbison mutant ( D’Agati et al, 2017 ).…”

In-depth study of MPV17: a molecular travel unveiling a mitochondrial calcium regulation function

“…SYM1, the yeast ortholog of MPV17, exhibits strong evolutionary conservation as its depletion can be complemented by human MPV17 expression which can rescue the impaired OXPHOS activity and growth defect under non-fermentable condition (Dallabona et al, 2010). SYM1 depletion leads to mitochondrial ultrastructure defects (Dallabona et al, 2010), as also observed in glomeruli cells of MPV17 -/--related kidney disease mouse model (Luna-Sanchez et al, 2020) and in mpv17 -/zebrafish larvae muscle (Bian et al, 2021). The maintenance of the mitochondrial ultrastructure is mainly achieved by the MItochondrial contact site and Cristae Organizing System (MICOS) complex, which is part of the Mitochondrial Intermembrane space Bridging (MIB) supercomplex.…”