Orchestrating mitochondrial protein import: The emerging role of DYRK1A in health and disease

The translocase of the outer mitochondrial membrane (TOM complex) serves as the central entry gate for more than 1000 nuclear-encoded precursor proteins imported into the organelle. Recently, the human import receptor TOM70 has been identified as a substrate of the serine/threonine kinase DYRK1A. DYRK1A activates the metabolite carrier import pathway, and its impairment triggers a transcriptional adaptive response that induces remodeling of the TOM complex. This compensatory mechanism activates additional import pathways to mitigate reduced DYRK1A signaling. Patients with dysfunctional DYRK1A signaling exhibit clinical manifestations that resemble classical features of mitochondriopathies. The emerging DYRK1A-TOM70 axis therefore represents a central signaling platform coordinating mitochondrial protein import pathways in health and disease.