Abstract
The function of AarF domain-containing kinase 1 (ADCK1) has not been thoroughly revealed. Here we identified that ADCK1 utilizes YME1-like 1 ATPase (YME1L1) to control optic atrophy 1 (OPA1) and inner membrane mitochondrial protein (IMMT) in regulating mitochondrial dynamics and cristae structure. We firstly observed that a serious developmental impairment occurred in Drosophila ADCK1 (dADCK1) deletion mutant, resulting in premature death before adulthood. By using temperature sensitive ubiquitously expression driver tub-Gal80ts/tub-Gal4 or muscle-specific expression driver mhc-Gal4, we observed severely defective locomotive activities and structural abnormality in the muscle along with increased mitochondrial fusion in the dADCK1 knockdown flies. Moreover, decreased mitochondrial membrane potential, ATP production and survival rate along with increased ROS and apoptosis in the flies further demonstrated that the structural abnormalities of mitochondria induced by dADCK1 knockdown led to their functional abnormalities. Consistent with the ADCK1 loss-of-function data in Drosophila, ADCK1 over-expression induced mitochondrial fission and clustering in addition to destruction of the cristae structure in Drosophila and mammalian cells. Interestingly, knockdown of YME1L1 rescued the phenotypes of ADCK1 over-expression. Furthermore, genetic epistasis from fly genetics and mammalian cell biology experiments led us to discover the interactions among IMMT, OPA1 and ADCK1. Collectively, these results established a mitochondrial signaling pathway composed of ADCK1, YME1L1, OPA1 and IMMT, which has essential roles in maintaining mitochondrial morphologies and functions in the muscle.
Highlights
The ADCK family proteins have common structural signatures of protein serine/threonine or tyrosine kinase and the evolutionarily conserved AarF domain
We unexpectedly found that AarF domain-containing kinase 1 (ADCK1) plays a crucial role in mitochondrial dynamics and cristae formation through interacting with critical mitochondrial proteins, such as YME1-like 1 ATPase (YME1L1), optic atrophy 1 (OPA1) and inner membrane mitochondrial protein (IMMT)
The human ADCKs were encoded by a gene family of ADCK1, ADCK2, ADCK3, ADCK4, and ADCK5, whereas the fly has a family of Adck (CG3608), CG32649, and CG7616
Summary
The ADCK family proteins have common structural signatures of protein serine/threonine or tyrosine kinase and the evolutionarily conserved AarF domain. The mutated form of ADCK3 is reported to be the main cause of cerebellar ataxia with seizures as well as decrease in motility [3, 4] Based on these isoform-specific functions, additional studies are needed to determine the functional roles of the other ADCK family proteins including ADCK1. The MICOS complex consists of many subunits and of these, IMMT ( known as MIC60) is recognized to be in the centre of the complex [10] It is well-known that IMMT participates in the formation of the cristae structure, its mechanism was unknown. If IMMT expression is suppressed, the assembly of the MICOS complex and the SAM complex is highly defected, and the cristae structures are reported to nearly disappear, resulting in a concentric circle-shaped inner membrane [15]. Abnormal YME1L1 has been revealed to be the direct cause of optic atrophy 11 [17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
