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Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium

An-a Kazuno1, Kae Munakata, Takeharu Nagai

  • 1Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Saitama, Japan.

Plos Genetics
|August 10, 2006
PubMed

Insights

Mitochondrial DNA (mtDNA) variations, specifically 8701A and 10398A, impact intracellular calcium and pH. These mtDNA polymorphisms may influence susceptibility to diseases like Parkinson's and Alzheimer's.

Area of Science:

  • Genetics
  • Cell Biology
  • Neuroscience

Background:

  • Mitochondrial DNA (mtDNA) exhibits high polymorphism, potentially influencing human health and disease susceptibility.
  • The precise impact of mtDNA variations on intracellular functions like calcium signaling and pH regulation remains largely unknown.

Purpose of the Study:

  • To identify mtDNA polymorphisms with intracellular functional significance.
  • To investigate the effects of specific mtDNA polymorphisms on mitochondrial calcium levels and matrix pH.

Main Methods:

  • Utilized transmitochondrial hybrid cells (cybrids) engineered with a fluorescent calcium indicator (ratiometric Pericam).
  • Analyzed the complete mtDNA sequence in 35 cybrid lines to correlate variations with functional readouts.
  • Measured mitochondrial matrix pH and assessed cytosolic calcium responses to histamine.

Main Results:

  • Identified two linked nonsynonymous mtDNA polymorphisms (8701A and 10398A) that elevated basal mitochondrial calcium levels.
  • Observed lower mitochondrial matrix pH in cybrids carrying 8701A/10398A compared to 8701G/10398G.
  • Found a trend towards higher cytosolic calcium responses to histamine in cybrids with 8701A/10398A.

Conclusions:

  • Specific mtDNA polymorphisms (8701A/10398A) alter mitochondrial calcium dynamics and matrix pH.
  • These functional changes provide a potential mechanism linking mtDNA variations to complex diseases like Parkinson's, Alzheimer's, and cancer.
  • The findings suggest a role for mtDNA polymorphisms in disease pathophysiology through modulation of intracellular signaling pathways.

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