# A Non-Invasive Approach to Intracellular Measurement in Solar Lentigo: Investigating Mitochondrial Dysfunction and Senescence Mechanisms Associated with Excessive Melanin Deposition

## TL;DR

This study explores how excessive melanin in skin cells causes mitochondrial dysfunction and cell aging in solar lentigo, using a non-invasive imaging technique.

## Contribution

A non-invasive in vivo method using FLIM to study mitochondrial and senescence changes in solar lentigo is introduced.

## Key findings

- Excessive melanin in keratinocytes reduces oxidative phosphorylation activity.
- Melanin accumulation induces senescence with altered cell cycle and inflammation.
- The study identifies a solar lentigo-specific senescence mechanism linked to melanin.

## Abstract

Solar lentigo is a significant dermatological concern affecting individuals of different genders and ethnicities. Its pathogenesis is primarily attributed to chronic ultraviolet (UV) exposure, increased melanogenesis, and disrupted epidermal turnover, leading to the development of hyperpigmented lesions. A major challenge in solar lentigo research is acquiring viable skin tissue, which is crucial for understanding the dynamics of the cellular microenvironment. In the present study, we sought to establish a non-invasive in vivo measurement technique to visualize cellular dynamics associated with solar lentigo. Utilizing fluorescence lifetime imaging microscopy (FLIM), we quantified the decay of NAD(P)H fluorescence lifetime and observed a reduction in oxidative phosphorylation (OXPHOS) activity in solar lentigo lesions compared to adjacent non-lesional skin. To determine whether the observed reduction in OXPHOS activity was due to excessive melanin accumulation in keratinocytes, we developed a melanin deposition model and examined the pleiotropic alterations occurring in keratinocytes following the phagocytosis of excessive melanin. Our findings indicate that excessive melanin deposition downregulates OXPHOS in differentiating keratinocytes and induces senescence-associated phenotypes characterized by perturbed cell cycle progression, increased cell size and aneuploidy, and the secretion of inflammatory mediators in proliferating keratinocytes. Collectively, our results implicate a solar lentigo-specific senescence mechanism driven by excessive melanin accumulation in keratinocytes, providing new insights about the intrinsic modulators of the pathological condition.