Zdhhc13-dependent Drp1 S-palmitoylation impacts brain bioenergetics, anxiety, coordination and motor skills

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.

Inhibition of Drp1 hyperactivation reduces neuropathology and behavioral deficits in zQ175 knock-in mouse model of Huntington's disease

“…Treatment of P110 reduced the anxiety-like behavior in zQ175 KI mice, indicating that Drp1-induced mitochondrial abnormality contributes to anxiety disorders in HD. Inhibition of Drp1 S-palmitoylation due to a Zdhhc13 recessive mutation in mouse model causes motor deficits and anxiety-related behaviors [40]. This line of evidence also supports the hypothesis that Drp1 hyperactivation contributes to anxiety disorders accompanied by HD.…”

Mitochondrial Morphofunction in Mammalian Cells

“…Mitochondrial fission and fusion proteins contain various (predicted) PTM sites, allowing their phosphorylation, Snitrosilation, sumoylation, ubiquitination, tyrosine sulfation, acetylation, and S-palmitoylation (5,70,279,425). Depending on the nature and location of the PTM, either mitochondrial fission or fusion is stimulated (51,103,289).…”

Beyond autophagy: a novel role for autism-linked Wdfy3 in brain mitophagy

“…Wdfy3 lacZ ( Wdfy3 tm1a(KOMP)Mbp ) mice were generated and genotyped as previously described 16 and maintained on C57BL/6NJ background as a mixed WT/heterozygous mutant colony in facilities approved by the Association for Assessment and Accreditation of Laboratory Animal Care International (AALAC). All mice were genotyped for Nnt as described before 68 (Supplementary Fig. S3 ).…”

“…After euthanasia, brains were dissected out of the skull and the cerebral hemispheres and cerebellum of each animal collected separately in ice-cold MSHE buffer (0.21 M mannitol, 0.07 M sucrose, 1 mM EDTA, 1 mM EGTA, 10 mM HEPES, pH 7.4). Subsequently, mitochondria were isolated by differential centrifugation as described before 68 . The mitochondrial fractions were heavily enriched with mitochondrial proteins presenting minimal contamination with cytosolic components (Fig.…”