An emerging profile: elevated autophagy and mitochondrial biogenesis may protect against mutant mitochondrial DNA

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NINDS	CELLBIO-12

Authors

• C.L. Nezich
• D.J. Ives
• R.J. Youle
• I.J. Holt

Abstract

Mitochondrial DNA (mtDNA) containing deleterious mutations can co-exist with wild-type (WT) molecules in a state of heteroplasmy. Some cell types display a clear bias towards mutant or WT mtDNA, but the molecular basis of selection is obscure. Recent evidence suggests that proteins involved in mitochondrial quality control (MQC) may be key determinants of this biased mtDNA segregation. Therefore, differential expression of MQC genes was analyzed in cell types known to segregate mutant and WT mtDNA oppositely. A549 adenocarcinoma cells, which select WT mtDNA, displayed elevated autophagic flux and high levels of two mitophagy-related proteins, compared to other cell lines. Attempting to increase mitophagy, and thus selection of WT mtDNA, by over-expressing PINK1 or Parkin in cells that do not ordinarily select for WT mtDNA, enriched for WT mtDNA in only a small minority of clones. Thus, if over-expressing PINK1 and Parkin increases mitophagy, then mitochondrial turnover must be insufficient to induce biased segregation. A549 cells also contain elevated mRNA levels of the transcriptional co-activator PGC1α relative to other cell types, suggesting that mitochondrial biogenesis and mitophagy may be inextricably linked to biased mtDNA segregation. Therefore, future studies will attempt to induce PGC1alpha in order to promote selection of WT mtDNA.

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