Alexander Kastaniotis

 

Short CV

Mitochondria and Lipids

Mitochondria are intracellular structures that are separated from the rest of the eukaryotic cell by a double membrane, forming a compartment specialized to perform a large array of task essential for cell survival. Most prominently, mitochondria convert breakdown products of sugars, fats or proteins into chemical energy that can be used by the cell, but there are several equally important other roles of these so-called cellular organelles. There is ample evidence that mitochondria descent from prokaryotic microbes that were incorporated into proto-eukaryotic cells eons ago and now exist in an endosymbiotic relationship with the rest of the cell. We are interested in the role of mitochondrial fatty acid synthesis (mtFAS) in the control of the function of these organelles. We have recently proposed that mtFAS serves as a regulatory circuit sensing the metabolic status of the cell and coordinating mitochondrial biogenesis and activity with cellular metabolite availability. Our studies in yeast and mammalian models, address the question on how this communication between the endosymbiotic resident and its cellular host is achieved on a molecular basis.

We recently participated in the first publication describing a novel human neurodegenerative disorder termed MEPAN (mitochondrial enoyl reductase protein associated neurodegeneration) caused by mutations in the MECR  gene, encoding 2-enoyl ACP reductase of mtFAS. We predict that patients with mutations in genes encoding other mtFAS components will display similar symptoms as the MEPAN patients, including childhood dystonia and optical atrophy. Interestingly, the most obvious neurological lesions in these patient appears to be restricted to the basal ganglia.

We have published a first report on a mouse Mecr knockout model in 2017. MECR is essential for mouse embryonic development and our data indicates that lack of MECR protein leads to placental failure in mice. A manuscript describing a mouse model in which Mecr deficiency leads to neurodegeneration has been accepted by the Journal of Neuroscience and will be in print in the beginning of November 2018. We are looking forward to using this model to investigate the mechanisms of mtFAS-defect related neurodegeneration and to test possible nutritional supplementation approaches to alleviate neurodegeneration symptoms.

Our work on mtFAS also led us to develop an interest in cellular protein partitioning. We have recently published our findings on a "cryptic" mitochondrial isoform of mammalian acetyl-CoA carboxylase ACC1. In this work, funded in part by by a "Trampoline" grant from the French AFM-Telethon organization (Association Francaise contre les Myopathies, http://www.afm-telethon.com/) during 2015/2016, we show that one isoform 1 of ACC1, which previously was thought to be exclusively localized to the cytosol, is present in the mitochondrial compartment. Our data indicates that ACC1 acts in tandem with the mitochondrial ACSF3 malonyl-CoA synthetase to generate the malonyl-CoA extender required for mtFAS.

Together with the brilliant research group lead by Joanna Kufel in Warsaw, Poland, we recently reported our findings from our studies on cryptic mitochondrial proteins. Our part in this work was initiated by AFM-Telethon funding when no other funding body believed that this was a project bearing any promise. We are very grateful to AFM-téléthon for funding risky, "out there" projects with their "Trampoline grant" program.

Our current work is supported by the Sigrid Juselius foundation, and by a four year Academy of Finland research project grant that started in September 2018.

We are located at the Kontinkangas Campus of the University of Oulu in Finland, close to the arctic circle. Many people looking up our location on the map believe that we must be covered in permafrost. This assumption does not hold true - while we do have beautiful winters with lots of snow, Oulu has proper four seasons and a beautiful sandy beach where people can enjoy a swim in the Gulf of Bonthnia in summer when it gets up to 30 degrees centrigrade here in the North. As a matter of fact, the summer of 2018 surprised us with subtropical temperatures over several weeks, with the asthmatic air conditioner in my office caving in, leaving me bathing in 32oC air of 90% humidity. In summer 2019, however, we seem to be back to a more cooler weather

Project details

  1. Background and Significance
  2. Selected Publications
  3. Research Group Members

Last updated: 21.8.2019