Studies reveal the mechanisms behind tumor metastasis and how to stymie it. But primary tumors still get the lion’s share of researchers’ attention.
Image courtesy of Science Source/Phanie.
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved March 7, 2016 (received for review November 16, 2015)
Significance
Microfluidic organ-on-a-chip technology is poised to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Here we demonstrate a sensor-integrated platform permitting real-time tracking of the dynamics of metabolic adaptation to mitochondrial dysfunction. Our approach permits detection of chemical toxicity before any effects on cell or tissue viability can be observed.
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 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.
Footnotes
↵1D.B. and S.P. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: ynahmias{at}cs.huji.ac.il.
Author contributions: Y.N. designed research; D.B., S.P., E.E., G.L., M.C., and Y.N. performed research; J.V. and M.J. contributed new reagents/analytic tools; D.B., S.P., E.E., G.L., M.V., and Y.N. analyzed data; and D.B., S.P., G.L., and Y.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1522556113/-/DCSupplemental.
Tracking dynamics of mitochondrial dysfunction
More Articles of This Classification
Related Content
Cited by...
Similar Articles
You May Also be Interested in
Both social and engineering factors must be further explored and scrutinized across the globe—as should notions of justice related to flooding impacts and responses.
Image courtesy of Shutterstock.com/Ekaterina Pokrovsky.
Blair Hedges discusses the state of Haiti's remaining forests and the consequences to biodiversity.
A study uncovers genetic evidence of early colonization of Jamaica by primates and suggests that adaptation can shape species morphology in novel environments, even when species come from morphologically conservative families.
Image courtesy of Lorraine Meeker (American Museum of Natural History, New York).
Researchers report that some moth species use sound absorbing-scales to avoid detection by bats and suggest that the findings could aid the design of biologically inspired sound absorbers for an array of applications, including noise mitigation and building acoustics.
Image courtesy of Thomas R. Neil.
