From Bedside to Bench in the Institute’s MRC Centre for Neuromuscular Diseases

'Back translation' provides new insights into mitochondrial biology

Researchers working at the Institute’s MRC Centre for Neuromuscular Diseases have made a potentially important discovery relevant to understanding both mitochondrial biology and human mitochondrial neurological disease. The research is a good example of “back-translation” in which careful research observations in patients can inform knowledge about normal biology.

The study was based on detailed clinical patient observation and biochemical stratification followed by whole exome next generation sequencing analysis. In combination with subsequent functional analysis, the work has provided compelling evidence which suggests we need to rethink the polypeptide structure of complex IV, one of the five enzyme complexes required for oxidative phosphorylation. Complex IV is the terminal enzyme of the mitochondrial respiratory electron transport chain and is critical for cellular energy (ATP) production.

The research team showed that pathogenic mutations in a gene called NDUFA4, previously considered to encode a subunit of complex I, can in fact cause severe complex IV deficiency leading to severe neurological mitochondrial disease.Original X-ray crystallography and biochemical studies have been the basis of the central widely accepted view that the NDUFA4 gene encodes a subunit of complex I. However, the MRC Centre’s discovery of a link between NDUFA4 mutations and human complex IV deficiency point to its role as a complex IV subunit.

This suggests that the long held view (present in all text books of biochemistry) that complex IV is composed of 13 polypeptide subunits needs to be revised, and that complex IV is in fact composed of 14 subunits. Furthermore, the NDUFA4 gene is now a candidate gene for unexplained complex IV deficiency in patients.

The team, led by Professor Michael G. Hanna, Dr Shamima Rahman and Dr Jan-Willem Taanman have published their findings in the current edition of Cell Reports:

Pitceathly, R. et al. (2013) NDUFA4 Mutations Underlie Dysfunction of a Cytochrome c Oxidase Subunit Linked to Human Neurological Disease. Cell Reports, 3(6), 1795–1805.   http://dx.doi.org/10.1016/j.celrep.2013.05.005

This work was an important part of the PhD thesis of Dr. Robert D.S. Pitceathly, a clinical research fellow at the Institute’s MRC Centre for Neuromuscular Diseases.