Abstract
Protein S-palmitoylation is a reversible post-translational modification mediated by palmitoyl acyltransferase enzymes, a group of Zn2+-finger DHHC-domain-containing proteins (ZDHHC). Here, for the first time, we show that Zdhhc13 plays a key role in anxiety-related behaviors and motor function, as well as brain bioenergetics, in a mouse model (luc) carrying a spontaneous Zdhhc13 recessive mutation. At 3 m of age, mutant mice displayed increased sensorimotor gating, anxiety, hypoactivity, and decreased motor coordination, compared to littermate controls. Loss of Zdhhc13 in cortex and cerebellum from 3- and 24 m old hetero- and homozygous male mutant mice resulted in lower levels of Drp1 S-palmitoylation accompanied by altered mitochondrial dynamics, increased glycolysis, glutaminolysis and lactic acidosis, and neurotransmitter imbalances. Employing in vivo and in vitro models, we identified that Zdhhc13-dependent Drp1 S-palmitoylation, which acting alone or in concert, enables the normal occurrence of the fission-fusion process. In vitro and in vivo direct Zdhhc13-Drp1 protein interaction was observed, confirming Drp1 as a substrate of Zdhhc13. Abnormal fission-fusion processes result in disrupted mitochondria morphology and distribution affecting not only mitochondrial ATP output but neurotransmission and integrity of synaptic structures in the brain, setting the basis for the behavioral abnormalities described in the Zdhhc13-deficient mice.
Highlights
Protein S-palmitoylation is a reversible post-translational modification mediated by palmitoyl acyltransferase (PAT) enzymes, a group of Zn2+-finger, Cys-rich DHHC-domain-containing proteins [Zdhhc1]
Given that (i) several mitochondrial proteins with clear roles in intermediary metabolism have been shown to be S-palmitoylated in a variety of biological systems[10,11,12] and (ii) alopecia—as observed in our[3] and another[12] mouse model of Zdhhc[13] deficiency—has been linked to mitochondrial dysfunction[13,14], we hypothesized that Zdhhc[13] loss-of-function would result in deficits in bioenergetics, not necessarily limited to skin, but to other highly aerobic organs such as brain resulting in behavioral deficits associated with energy distress and altered metabolism of neurotransmitters
Our results indicated that Zdhhc[13], acting via S-palmitoylation of Drp[1], alone or acting in concert, is critical for sustaining cortex and cerebellum mitochondrial dynamics and function resulting in deficits in motor- and non-motor skills
Summary
Protein S-palmitoylation is a reversible post-translational modification mediated by palmitoyl acyltransferase (PAT) enzymes, a group of Zn2+-finger, Cys-rich DHHC-domain-containing proteins [Zdhhc1]. Deficits in Zdhhc[17] (one of the 23 or 24 PATs from human and rat or mouse, respectively) are associated with behavioral, memory and synaptic defects[4,5] based on the palmitoylation of substrates relevant to neurogenesis and neurotransmission (e.g. SNAP-25, synaptotagmin I, and huntingtin (Htt)[4,6]). To date, limited information is available on the functional connection between behavioral deficits and the substrates for these PATs. Recently, we described the luc mice, carrying a naturally occurring recessive mutation on Zdhhc[133]. While several studies have reported complete S-palmitoylomes, very few have identified specific PAT substrates, the effect of this post-translational modification on the target’s function and the impact of this change at the whole organism level (behavior)
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