Skin manifestations of mitochondrial dysfunction: more important than previously thought

Mitochondrial DNA (mtDNA) research is emerging within the dermatological field as a unique biomarker for diagnostic, prognostic and even therapeutic exploration. As the first review of the role of mtDNA in skin disease was authored by our group some 14 years ago 1, there have been many exciting observations linking mitochondria to the defective structural, cell signalling and oxidative damage pathways that promote skin disease manifestation. Feichtinger et al. 2 have compiled an extensive and interesting review of recent literature that examines the relationship between known molecular paradigms of skin disease and intrinsic mitochondrial health. Whilst it is unrealistic for the authors to fully explore all recent advances within normal journal constraints, there are some surprising omissions, including our own detailed review of mtDNA and skin disease in 2000. Feichtinger et al. 2 highlight the breadth of potential mitochondrial involvement in conditions not traditionally associated with metabolic or oxidative phosphorylation defects. On consideration, however, it seems intuitive that any global defect of cell function is capable of exerting detrimental secondary effects on mitochondrial function. An example of this is mutation of the keratin 5 and 14 genes which are associated with the dermatological manifestation (e.g. skin blistering) of epidermolysis bullosa simplex. The altered mitochondrial network formation highlighted by Feichtinger et al. 2 is likely to be a secondary factor in disease causation. Nonetheless, such mitochondrial aspects warrant investigation as potential therapeutic and prognostic markers within the context of wider disease state aetiologies. Mitochondria are the major site of ATP generation within cells. Five enzyme complexes are involved in the generation of the energy currency molecule ATP. Complexes I–IV form the mitochondrial electron transport chain (mETC), whose primary function is the generation and maintenance of an electromotive proton gradient across the inner mitochondrial membrane as summarized in Fig. 1. Succinate dehydrogenase (Complex II) forms an important ‘metabolic bridge’ by performing a duel role as both a proximal mETC component and as an element of the tricarboxylic acid (TCA) cycle. It is known that several mtDNA mutations affecting genes encoding mETC components are complicit in defective mitochondrial function [recently reviewed in 3]. Cells contain many copies of the mitochondrial genome and as such may contain a ratio of mutant or damaged mtDNA to wild-type or undamaged mtDNA (termed ‘heteroplasmy’). The threshold of tolerable accumulated damage can be breached over time, ultimately leading to the disease state manifestation [reviewed in 4]. Feichtinger et al. 2 present several skin diseases involving mtDNA mutations; however, discussion regarding the important effects of heteroplasmy with regard to disease development is missing possibly due to space constraints. Heteroplasmic effects are of critical importance, as mtDNA mutations may not be significant to cause a disease when present at only low levels within a cell 4. The occurrence of heteroplasmy within the mitochondria allows damage to accumulate to a point without affecting mitochondrial function. This, along with limited repair mechanisms and lack of histone body association, permits the use of mtDNA as a reliable biomarker for damage accumulation in both human and animal skin (4, 6,S1). Mutation in a nuclear or mitochondrial gene encoding a mETC subunit causes mitochondrial dysfunction; however, impaired mtDNA maintenance, defects in mitochondrial translation factors and other indirect mechanisms can also manifest disease states (reviewed in (S2)). In 2013, mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) were first demonstrated that cleave different classes of pathogenic mtDNA in dermal fibroblast cybrids (S3). Such mitoTALEN technology may present a novel therapeutic tool for targeting skin manifestations of mitochondrial disease. Constant exposure to solar radiation, chemical and mechanical stresses places unique repair and protection pressures upon the skin compared to other organs. The damaging effects of UV irradiation upon mitochondrial damage and function in skin have been the subject of intensive recent investigation (4, 5,S1,S4). From our pioneering observation reported at the ESDR in 1996, the importance of using mtDNA as a reliable and sensitive biomarker of sun exposure has been successfully exploited by our group and many others within dermatological areas including ageing and cancer [reviewed in (6,S5)]. In addition, oxidative stress-induced mtDNA damage in skin cells has recently been used as a tool for assessing the potency of cell and mitochondria–targeted antioxidants 7 and has potential for screening therapeutic compounds including antioxidants used in cosmetics and the diet. This is alluded to by Feichtinger et al. 2 who highlight nicotinamide (vitamin B3) a compound which, as a precursor of nicotinamide adenine dinucleotide within mitochondrial energy metabolism, has provided benefit by reducing actinic keratosis (S6) and mitochondrial myopathy (S7). Feichtinger et al. 2 also briefly mention the therapeutic targeting of mitochondria in skin disease using the drug dithranol as a treatment for psoriasis. The mechanism of action was described as ‘damaging’ to mitochondria via the uncoupling of ATP production (2,S8). More recently, dithranol's mechanism of action has been elucidated (S9). The drug interacts specifically with the mitochondrial ubiquinone pool in keratinocyte cells subsequently inducing apoptosis by mitochondrial membrane potential disruption, causing a release in cytochrome c. This action is dependent upon the presence of a functional mETC (S9). In the respect of a functional mETC, Feichtinger et al. 2 have highlighted the important potential roles of individual mETC complexes in various skin diseases; however, Complex II was not explored. This often over-looked complex was recently implicated in the ageing process of both human (S10) and mouse skin (S11). It was also reported to produce reactive oxygen species (ROS) to a similar extent as Complexes I and III (8,S12,S13). The authors concluded that Complex II may be more important than previously thought. Mutant Complex II subunits have been shown to increase ROS generation (S14–S17), whilst Complex II ROS flux has also been shown to prevent cell cycle progress, inferring association with senescence induction (S18). Complex II's unique ‘metabolic hinge’ role in both the TCA cycle and the mETC dictates that the importance of this complex is not to be underestimated. Further elucidation of Complex II's impact will provide a more complete picture of mitochondrial involvement in skin disease. Without doubt, alterations in mitochondrial status and function impact skin health, although it is difficult to elucidate the individual contributions of UV irradiation, chemical insult, injury and genetic predisposition over a lifetime of stress and strain. Technological developments regarding real-time methods of ROS formation monitoring and miniaturized tools for mitochondrial analysis are pushing the boundaries of novel mitochondrial investigations and insight (9,S19). It is important that the momentum of skin-directed mitochondrial research is maintained, pioneering the research of biomarkers, aetiologies and potential therapeutic strategies for the cure and prevention of such highly visible and life-limiting diseases. The Research was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. All authors contributed to writing the paper. The authors report no conflicting interests. S1. Swalwell H, Latimer J, Haywood R M et al. Free Radic Biol Med 2012: 52: 626–634. S2. Ylikallio E, Suomalainen A. Ann Med 2012: 44: 41–59. S3. Bacman S R, Williams S L, Pinto M et al. Nat Med 2013: 19: 1111–1113. S4. Jantschitsch C, Trautinger F. Photochem Photobiol Sci 2003: 2: 899–903. S5. Birch-Machin M A, Russell E V, Latimer J A. B J Dermatol 2013: 169 Suppl 2: 9–14. S6. Surjana D, Halliday G M, Martin A J et al. J Invest Dermatol 2012: 132: 1497–1500. S7. Khan N A, Auranen M, Paetau I et al. EMBO Mol Med 2014: 6: 721–731. S8. Morliere P, Dubertret L, Sa e Melo T et al. BJ Dermatol 1985: 112: 509–515. S9. McGill A, Frank A, Emmett N et al. FASEB J 2005: 19: 1012–1014. S10. Bowman A, Anderson A, Manning P et al. B J Dermatol 2014: 170: e10. S11. Velarde M C, Flynn J M, Day N U et al. Aging 2012: 4: 3–12. S12. Guo J, Lemire B D. J Biol Chem 2003: 28: 47629–47635. S13. Lemarie A, Huc L, Pazarentzos E et al. Cell Death Differ 2011: 18:338–349. S14. Ishii N, Senoo-Matsuda N, Miyake K et al. Mech Ageing Dev 2004: 125:41–46. S15. Walker D W, Hajek P, Muffat J et al. Proc Natl Acad Sci USA 2006: 103: 16382–16387. S16. Ishii T, Yasuda K, Akatsuka A et al. Cancer Res 2005: 65:203–209. S17. Slane B G, Aykin-Burns N, Smith B J et al. Cancer Res 2006: 66:7615–7620. S18. Byun H O, Kim H Y, Lim J J et al. J Cell Biochem 2008: 104(S1):1747–1759. S19. Boulton S J, Birch-Machin M. Melanin reduces acute mitochondrial superoxide generation: a real-time amperometric study. In: British Journal Of Dermatology: Wiley-Blackwell 111 River St, Hoboken 07030-5774, NJ USA, 2014: E33–E33.

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