Disease-Associated Genetic Variation in Human Mitochondrial Protein Import

Am J Hum Genet. 2019 May 2;104(5):784-801. doi: 10.1016/j.ajhg.2019.03.019.


Mitochondrial dysfunction has consequences not only for cellular energy output but also for cellular signaling pathways. Mitochondrial dysfunction, often based on inherited gene variants, plays a role in devastating human conditions such as mitochondrial neuropathies, myopathies, cardiovascular disorders, and Parkinson and Alzheimer diseases. Of the proteins essential for mitochondrial function, more than 98% are encoded in the cell nucleus, translated in the cytoplasm, sorted based on the presence of encoded mitochondrial targeting sequences (MTSs), and imported to specific mitochondrial sub-compartments based on the integrated activity of a series of mitochondrial translocases, proteinases, and chaperones. This import process is typically dynamic; as cellular homeostasis is coordinated through communication between the mitochondria and the nucleus, many of the adaptive responses to stress depend on modulation of mitochondrial import. We here describe an emerging class of disease-linked gene variants that are found to impact the mitochondrial import machinery itself or to affect the proteins during their import into mitochondria. As a whole, this class of rare defects highlights the importance of correct trafficking of mitochondrial proteins in the cell and the potential implications of failed targeting on metabolism and energy production. The existence of this variant class could have importance beyond rare neuromuscular disorders, given an increasing body of evidence suggesting that aberrant mitochondrial function may impact cancer risk and therapeutic response.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Humans
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondrial Diseases / physiopathology*
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Protein Transport


  • Mitochondrial Membrane Transport Proteins
  • Molecular Chaperones