Expression and maintenance of mitochondrial DNA: new insights into human disease pathology

Am J Pathol. 2008 Jun;172(6):1445-56. doi: 10.2353/ajpath.2008.071163. Epub 2008 May 5.


Mitochondria are central players in cellular energy metabolism and, consequently, defects in their function result in many characterized metabolic diseases. Critical for their function is mitochondrial DNA (mtDNA), which encodes subunits of the oxidative phosphorylation complexes essential for cellular respiration and ATP production. Expression, replication, and maintenance of mtDNA require factors encoded by nuclear genes. These include not only the primary machinery involved (eg, transcription and replication components) but also those in signaling pathways that mediate or sense alterations in mitochondrial function in accord with changing cellular needs or environmental conditions. Mutations in these contribute to human disease pathology by mechanisms that are being revealed at an unprecedented rate. As I will discuss herein, the basic protein machinery required for transcription initiation in human mitochondria has been elucidated after the discovery of two multifunctional mitochondrial transcription factors, h-mtTFB1 and h-mtTFB2, that are also rRNA methyltransferases. In addition, involvement of the ataxia-telangiectasia mutated (ATM) and target of rapamycin (TOR) signaling pathways in regulating mitochondrial homeostasis and gene expression has also recently been uncovered. These advancements embody the current mitochondrial research landscape, which can be described as exploding with discoveries of previously unanticipated roles for mitochondria in human disease and aging.

Publication types

  • Lecture
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / genetics
  • Aging / physiology*
  • Animals
  • Ataxia Telangiectasia / genetics
  • Ataxia Telangiectasia / metabolism
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / physiology
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / physiology*
  • DNA-Binding Proteins / physiology
  • Gene Expression Regulation
  • Humans
  • Methyltransferases / physiology
  • Mitochondrial Diseases / etiology
  • Mitochondrial Diseases / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mitochondrial Proteins / physiology
  • Mutation
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphotransferases (Alcohol Group Acceptor) / physiology
  • Protein Serine-Threonine Kinases / physiology
  • Saccharomyces cerevisiae Proteins / physiology
  • Signal Transduction
  • Transcription Factors / physiology
  • Tumor Suppressor Proteins / physiology


  • Cell Cycle Proteins
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • Saccharomyces cerevisiae Proteins
  • TFB1M protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Methyltransferases
  • TFB2M protein, human
  • rRNA (adenosine-O-2'-)methyltransferase
  • Phosphotransferases (Alcohol Group Acceptor)
  • TOR1 protein, S cerevisiae
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases