Real-time monitoring of metabolic function in liver-onchip microdevices tracks the dynamics of Mitochondrial dysfunction

Danny Bavli, Sebastian Prill, Elishai Ezra, Gahl Levy, Merav Cohen, Mathieu Vinken, Jan Vanfleteren, Magnus Jaeger, Yaakov Nahmias*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

240 Scopus citations

Abstract

Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liveron-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology.

Original languageAmerican English
Pages (from-to)E2231-E2240
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number16
DOIs
StatePublished - 19 Apr 2016

Keywords

  • Liver tissue engineering
  • Microfluidics
  • Organ-on-a-chip
  • Toxicology

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