Mitochondria Profoundly Influence Apolipoprotein E Biology

J Alzheimers Dis. 2023;92(2):591-604. doi: 10.3233/JAD-221177.

Abstract

Background: Mitochondria can trigger Alzheimer's disease (AD)-associated molecular phenomena, but how mitochondria impact apolipoprotein E (APOE; apoE) is not well known.

Objective: Consider whether and how mitochondrial biology influences APOE and apoE biology.

Methods: We measured APOE expression in human SH-SY5Y neuronal cells with different forms of mitochondrial dysfunction including total, chronic mitochondrial DNA (mtDNA) depletion (ρ0 cells); acute, partial mtDNA depletion; and toxin-induced mitochondrial dysfunction. We further assessed intracellular and secreted apoE protein levels in the ρ0 cells and interrogated the impact of transcription factors and stress signaling pathways known to influence APOE expression.

Results: SH-SY5Y ρ0 cells exhibited a 65-fold increase in APOE mRNA, an 8-fold increase in secreted apoE protein, and increased intracellular apoE protein. Other models of primary mitochondrial dysfunction including partial mtDNA-depletion, toxin-induced respiratory chain inhibition, and chemical-induced manipulations of the mitochondrial membrane potential similarly increased SH-SY5Y cell APOE mRNA. We explored potential mediators and found in the ρ0 cells knock-down of the C/EBPα and NFE2L2 (Nrf2) transcription factors reduced APOE mRNA. The activity of two mitogen-activated protein kinases, JNK and ERK, also strongly influenced ρ0 cell APOE mRNA levels.

Conclusion: Primary mitochondrial dysfunction either directly or indirectly activates APOE expression in a neuronal cell model by altering transcription factors and stress signaling pathways. These studies demonstrate mitochondrial biology can influence the biology of the APOE gene and apoE protein, which are implicated in AD.

Keywords: APOE; Alzheimer’s disease; apolipoprotein E; mitochondria; mitochondrial DNA.

Publication types

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

MeSH terms

  • Alzheimer Disease* / metabolism
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Biology
  • Cell Line, Tumor
  • DNA, Mitochondrial / genetics
  • Humans
  • Mitochondria / metabolism
  • Neuroblastoma* / metabolism
  • RNA, Messenger / metabolism
  • Transcription Factors / metabolism

Substances

  • DNA, Mitochondrial
  • Apolipoproteins E
  • Transcription Factors
  • RNA, Messenger