Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction
| Autor: | Magnus S. Jaeger, Elishai Ezra, Danny Bavli, Gahl Levy, Yaakov Nahmias, Merav Cohen, Sebastian Prill, Jan Vanfleteren, Mathieu Vinken |
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| Přispěvatelé: | Publica, Pharmaceutical and Pharmacological Sciences, Connexin Signalling Research Group, Liver Connexin and Pannexin Research Group, Experimental in vitro toxicology and dermato-cosmetology |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Mitochondrial Diseases liver tissue engineering Cellular adaptation TOXICOLOGY Microfluidics Mitochondria Liver Nanotechnology 02 engineering and technology Oxidative phosphorylation Biology HEPATOCYTES Organ-on-a-chip Troglitazone 03 medical and health sciences Oxygen Consumption Lab-On-A-Chip Devices medicine Humans Atp production Chromans organ-on-a-chip Multidisciplinary Metabolic function Biology and Life Sciences PATHWAYS Hep G2 Cells 021001 nanoscience & nanotechnology Cell biology DIFFERENTIATION 030104 developmental biology PNAS Plus Liver Anaerobic glycolysis Toxicity Thiazolidinediones 0210 nano-technology INTEGRATION toxicology medicine.drug |
| Zdroj: | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Europe PubMed Central |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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 liver-on-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. |
| Databáze: | OpenAIRE |
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