From the cytosol to the inner membrane: biogenesis of the mitochondrial carrier family

Mitochondrial carrier proteins are essential for cellular physiology as they are active in a wide range of metabolic pathways including production of cellular energy, amino acid synthesis, redox balance and ion homeostasis. The double membrane of mitochondria provides a tightly gated environment through which carrier proteins facilitate the exchange of substrates including nucleotides, ions, metabolites, cofactors and vitamins. The biogenesis of the carrier family relies on the coordinated action of the TOM and TIM22 complexes, which direct the translocation of nuclear-encoded precursors across the outer membrane (TOM) and their integration into the mitochondrial inner membrane (TIM22). Due to the intrinsic hydrophobicity of the carrier precursors, their import pathway requires chaperones in both the cytosol and intermembrane space to maintain solubility and prevent aggregation during transit. Given their central role in metabolism, dysfunction of the biogenesis machinery or the carrier proteins has serious consequences to human health. In this review we summarize the current understanding of carrier protein biogenesis in human cells and highlight how perturbations to this pathway influence human health.