Mitochondria are commonly known as the powerhouses of cells. However, they contribute much more to cellular function than just the production of energy. Mitochondria regulate levels of calcium, an essential component of cellular communication, control programmed cell death, and even contain their own DNA. Mutations in mitochondrial DNA (“mtDNA”) are associated with numerous genetic disorders, including Leigh syndrome and MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), and defects in mitochondrial function are implicated in many other disorders, such as bipolar disorder, ALS, and some cancers. With mitochondria responsible for a wide variety of processes and their dysfunction implicated in an ever-increasing number of disorders, understanding the mutations in both mtDNA and cellular DNA that affect mitochondrial function is essential.
Cellular DNA, the genetic blueprint that codes for all the proteins in the body, is inherited from both the mother and father. Mitochondrial DNA, however, was believed to only be passed down from the mother. A recent publication from researchers at Cincinnati Children’s Hospital Medical Center provides substantial evidence that this long-held belief may not always be true. The authors examined the mtDNA of a young patient suspected to have a mitochondrial disorder. While they found nothing suggestive of such a disorder, the patient’s mtDNA showed distinct differences in sequence at an abnormally high number of locations within the genes. These variations were identified by comparing the mitochondrial sequence to a standard known as the “revised Cambridge Reference Sequence” or rCRS. The authors extended their genetic analysis to members of the patient’s family, concluding that two distinct groups of mutations were inherited from the maternal grandmother and grandfather. Continuing this analysis in the parents of the maternal grandfather showed a similar biparental inheritance pattern. The sequencing was repeated at two other independent labs, since contamination could have caused these unexpected results. Two other, unrelated families with high levels of variation in their mtDNA were analyzed and in these families, there is clear evidence for inheritance of mtDNA from both parents as well.
The potential implications of this study are far-reaching. Any previous DNA sequence analysis yielding similar results was commonly assumed to be due to contamination or sample mix-up. It is possible that paternal inheritance of mtDNA is more widespread than even the results of this study suggest. From a biological standpoint, the mechanism underlying this inheritance pattern is completely unknown, and could be due to mutations in mtDNA, cellular DNA, or both. In humans, paternal mitochondria are eliminated after fertilization, though it is essential that sperm cells contain mitochondria beforehand to power their motion. It seems likely that some mutation in this process allows both the survival of paternal mitochondria and an increase in their numbers to levels comparable to the maternal population. Finally, and perhaps most interestingly, this could potentially have pronounced implications for medicine. Preventing the inheritance of pathogenic mutations from the maternal mtDNA has been difficult, but if this paternal inheritance mechanism can be understood and employed in embryos at risk for mitochondrial disorders, it may be possible to more effectively treat some of the large number of disorders associated with mitochondrial dysfunction.
Managing Correspondent: Andrew T. Sullivan
Press Articles: Fathers Can Pass Mitochondrial DNA to Children, TheScientist
Original Journal Article: Biparental Inheritance of Mitochondrial DNA in Humans, PNAS