Control of the mitochondrial carrier import pathway by DYRK1A

Mitochondria require a complete and functional proteome to maintain a plethora of metabolic reactions in a cell. Changes in cellular demands depend on a rapid adaptation of the mitochondrial proteome. The translocase of the outer membrane TOM, constitutes the organellar entry gate that imports nearly all proteins as precursors from the cytosol. It is therefore an ideal target for cytosolic signalling pathways to regulate organellar protein influx. Here we identify the human mitochondrial import receptor TOM70 as a target of the cytosolic kinase DYRK1A. Phosphorylation of TOM70Ser91 by DYRK1A does not affect precursor binding but stimulates the interaction of the peripheral import receptor with the core TOM complex to enable increased precursor translocation. Thus TOM70Ser91 phosphorylation by DYRK1A provides a regulatory switch for the carrier import pathway in human mitochondria. DYRK1A has not been linked to mitochondria before. Regulation of protein import by DYRK1A provides an efficient mean to adapt the mitochondrial proteome to changing cellular needs and may also build a basis for the understanding of disease mechanisms caused by dysfunctional DYRK1A.