Novel imaging biomarkers for mapping the impact of mild mitochondrial uncoupling in the outer retina in vivo

Autoři: Bruce A. Berkowitz aff001;  Hailey K. Olds aff001;  Collin Richards aff001;  Joydip Joy aff001;  Tilman Rosales aff001;  Robert H. Podolsky aff002;  Karen Lins Childers aff002;  W. Brad Hubbard aff003;  Patrick G. Sullivan aff003;  Shasha Gao aff006;  Yichao Li aff006;  Haohua Qian aff006;  Robin Roberts aff001
Působiště autorů: Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, United States of America aff001;  Beaumont Research Institute, Beaumont Health, Royal Oak, MI, United States of America aff002;  Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, United States of America aff003;  Department of Neuroscience, University of Kentucky, Lexington, KY, United States of America aff004;  Lexington VA Health Care System, Lexington, KY, United States of America aff005;  Visual Function Core, National Eye Institute, National Institutes of Health, Bethesda, MD, United States of America aff006;  Department of Ophthalmology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China aff007
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article



To test the hypothesis that imaging biomarkers are useful for evaluating in vivo rod photoreceptor cell responses to a mitochondrial protonophore.


Intraperitoneal injections of either the mitochondrial uncoupler 2,4 dinitrophenol (DNP) or saline were given to mice with either higher [129S6/eVTac (S6)] or lower [C57BL/6J (B6)] mitochondrial reserve capacities and were studied in dark or light. We measured: (i) the external limiting membrane–retinal pigment epithelium region thickness (ELM-RPE; OCT), which decreases substantially with upregulation of a pH-sensitive water removal co-transporter on the apical portion of the RPE, and (ii) the outer retina R1 (= 1/(spin lattice relaxation time (T1), an MRI parameter proportional to oxygen / free radical content.


In darkness, baseline rod energy production and consumption are relatively high compared to that in light, and additional metabolic stimulation with DNP provoked thinning of the ELM-RPE region compared to saline injection in S6 mice; ELM-RPE thickness was unresponsive to DNP in B6 mice. Also, dark-adapted S6 mice given DNP showed a decrease in outer retina R1 values compared to saline injection in the inferior retina. In dark-adapted B6 mice, transretinal R1 values were unresponsive to DNP in superior and inferior regions. In light, with its relatively lower basal rod energy production and consumption, DNP caused ELM-RPE thinning in both S6 and B6 mice.


The present results raise the possibility of non-invasively evaluating the mouse rod mitochondrial energy ecosystem using new DNP-assisted OCT and MRI in vivo assays.

Klíčová slova:

Biomarkers – Eyes – In vivo imaging – Magnetic resonance imaging – Mitochondria – Oxygen – Retina – Tomography


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