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Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis

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Science Translational Medicine  30 Nov 2016:
Vol. 8, Issue 367, pp. 367ra169
DOI: 10.1126/scitranslmed.aag2202

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Mitochondria expose tumors’ misbehavior

Mitochondria, the powerhouses inside cells, change their shape and function according to the needs of the cell. Such mitochondrial dynamics go awry in a variety of human diseases, and if these abnormalities are detected early, they can be useful for diagnosis and fast treatment. Now, Pouli et al. show that such signs of mitochondrial dysfunction can be spotted in living human skin with two-photon–excited fluorescence by monitoring the mitochondrial metabolic coenzyme NADH. The authors detected rapid changes in mitochondrial organization in response to oxygen deprivation and successfully distinguished healthy skin from two common skin cancers—basal cell carcinoma and melanoma.


Active changes in mitochondrial structure and organization facilitate cellular homeostasis. Because aberrant mitochondrial dynamics are implicated in a variety of human diseases, their assessment is potentially useful for diagnosis, therapy, and disease monitoring. Because current techniques for evaluating mitochondrial morphology are invasive or necessitate mitochondria-specific dyes, their clinical translation is limited. We report that mitochondrial dynamics can be monitored in vivo, within intact human skin by relying entirely on endogenous two-photon–excited fluorescence from the reduced metabolic coenzyme nicotinamide adenine dinucleotide (NADH). We established the sensitivity of this approach with in vivo, fast temporal studies of arterial occlusion-reperfusion, which revealed acute changes in the mitochondrial metabolism and dynamics of the lower human epidermal layers. In vitro hypoxic-reperfusion studies validated that the in vivo outcomes were a result of NADH fluorescence changes. To demonstrate the diagnostic potential of this approach, we evaluated healthy and cancerous human skin epithelia. Healthy tissues displayed consistent, depth-dependent morphological and mitochondrial organization patterns that varied with histological stratification and intraepithelial mitochondrial protein expression. In contrast, these consistent patterns were absent in cancerous skin lesions. We exploited these differences to successfully differentiate healthy from cancerous tissues using a predictive classification approach. Collectively, these results demonstrate that our label-free, automated, near real-time assessments of mitochondrial organization—relying solely on endogenous contrast—could be useful for accurate, noninvasive in vivo diagnosis.

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