Anticancer DNA intercalators cause p53-dependent mitochondrial DNA nucleoid re-modelling.

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Anticancer drugs, such as doxorubicin (DXR), are known to intercalate into nuclear DNA, inhibiting cancer cell growth.
• The interaction of these DNA intercalators with mitochondrial DNA (mtDNA) is not well understood.

Purpose of the Study:

• To investigate how DNA intercalators interact with mtDNA within living cells.
• To elucidate the cellular response to DNA intercalator-induced mtDNA damage.

Main Methods:

• Cell and molecular studies using cultured cells.
• Analysis of mitochondrial DNA nucleoid structure and protein distribution.
• Investigation of mitochondrial morphology and fusion proteins (mitofusin 1, OPA1).
• Assessment of the role of p53 and ATM in the response.

Main Results:

• DNA intercalators rapidly intercalate into mtDNA, causing nucleoid aggregation and altered protein distribution.
• Mitochondrial DNA nucleoids remodel to exclude intercalators and maintain synthesis, while non-remodelled nucleoids experience replication inhibition and mtDNA depletion.
• Mitochondrial remodeling is linked to mitochondrial elongation/interconnection and suppressed by defects in mitochondrial fusion proteins (mitofusin 1, OPA1).
• p53 or ATM inhibition enhances nucleoid remodeling, suggesting a link to the genomic DNA damage response.

Conclusions:

• DNA intercalators trigger a common mitochondrial response involving nucleoid remodeling and altered mitochondrial dynamics.
• This mitochondrial response may contribute to the clinical toxicity observed with DNA intercalating anticancer drugs.