Mitochondrial Dynamics in Skin Health and Disease: Energy, Ageing, and Therapeutic Perspectives

Cancer treatments in general share various detrimental effects in common, especially upregulation of cardiovascular risk factors. Therefore, the science of onco-cardiology should not be restricted in scope to the side effects of each specific cancer drug. In particular, premature aging induced by cancer treatment may contribute to the chronic health problems of cancer survivors. About 1 660 000 people, including more than 12 000 children below the age of 18 years, are newly diagnosed with a malignancy in the United States every year.1 The American Cancer Society reported that in 2016 there are 15.5 million cancer survivors in the United States (http://www.cancer.org/cancer/news/news/report-number-of-cancer-survivors-continues-to-grow). At present, the 5-year survival rate of patients treated for cancer is 67%. Seventy-five percent of children in whom cancer is diagnosed today will live for at least 10 years; 20% will survive for longer than 35 years.1 Although these numbers are impressive compared with those from decades ago, further improvement of cancer survivors’ life span as well as quality of life and functional status is still necessary. Approximately 75% of cancer survivors have some form of chronic health problem. Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in this population, particularly after recurrent or second malignancy. The risk of CVD in cancer survivors is 8× higher than that of the general population. The relative risks of coronary artery disease and heart failure in cancer survivors are 10× and 15× higher, respectively, than their siblings without cancer.1 Cancer treatments, including chemotherapy and radiation, can lead to both short- and long-term cardiovascular complications. Evidence of subclinical cardiac and vascular damage was observed in more than 50% of survivors 5 to 10 years after chemotherapy.1 Onco-cardiology is a medical subspecialty concerned with the diagnosis and treatment of CVDs and organ failure mediated by microcirculatory or macrocirculatory …

The clinical correlations linking diabetes mellitus with accelerated atherosclerosis, cardiomyopathy, and increased post-myocardial infarction fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in reactive oxygen species (ROS) production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP-ribose) polymerase, which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and poly(ADP-ribose) polymerase also reduce sirtuin, PGC-1α, and AMP-activated protein kinase activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of proatherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, peptidylarginine deiminase 4, and activates the NOD-like receptor family, pyrin domain-containing 3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of forkhead box O 1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after myocardial infarction by increasing post-translational protein modifications, which cause increased ryanodine receptor phosphorylation and downregulation of sarco-endoplasmic reticulum Ca(++)-ATPase transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor α3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy.

Mitochondria are dynamic organelles that continuously change their shape through fission and fusion. Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species (ROS) production. Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Hence, we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBEC). Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy. Senescence-associated β-galactosidase staining and p21 Western blotting of primary HBEC were performed to evaluate cellular senescence. Mitochondrial-specific superoxide production was measured by MitoSOX staining. Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins (OPA1 or Mitofusins) by small-interfering RNA transfection. N-acetylcysteine and Mito-TEMPO were used as antioxidants. Mitochondria in bronchial epithelial cells were prone to be more fragmented in COPD lung tissues. CSE induced mitochondrial fragmentation and mitochondrial ROS production, which were responsible for acceleration of cellular senescence in HBEC. Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells. HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants. CSE-induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production. Hence, disruption of mitochondrial dynamics may be a part of the pathogenic sequence of COPD development.

Alternative Ways to Die5Epac1 deletion prevents cardiomyocyte apoptosis during ischemia/reperfusion6Subcellular redistribution of mitogen and stress activated kinase 1 (MSK1) contributes to protection against oxidative stress- induced apoptosis in cardiac myocytes7Excessive ROS production in mitochondria switches off protective mitochondrial kinase signaling

Hypertension is associated with excessive reactive oxygen species (ROS) production in vascular cells. Mitochondria undergo fusion and fission, a process playing a role in mitochondrial function. OPA1 is essential for mitochondrial fusion. Loss of OPA1 is associated with ROS production and cell dysfunction. We hypothesized that mitochondria fusion could reduce oxidative stress that defect in fusion would exacerbate hypertension. Using (a) Opa1 haploinsufficiency in isolated resistance arteries from Opa1+/- mice, (b) primary vascular cells from Opa1+/- mice, and (c) RNA interference experiments with siRNA against Opa1 in vascular cells, we investigated the role of mitochondria fusion in hypertension. In hypertension, Opa1 haploinsufficiency induced altered mitochondrial cristae structure both in vascular smooth muscle and endothelial cells but did not modify protein level of long and short forms of OPA1. In addition, we demonstrated an increase of mitochondrial ROS production, associated with a decrease of superoxide dismutase 1 protein expression. We also observed an increase of apoptosis in vascular cells and a decreased VSMCs proliferation. Blood pressure, vascular contractility, as well as endothelium-dependent and -independent relaxation were similar in Opa1+/- , WT, L-NAME-treated Opa1+/- and WT mice. Nevertheless, chronic NO-synthase inhibition with L-NAME induced a greater hypertension in Opa1+/- than in WT mice without compensatory arterial wall hypertrophy. This was associated with a stronger reduction in endothelium-dependent relaxation due to excessive ROS production. Our results highlight the protective role of mitochondria fusion in the vasculature during hypertension by limiting mitochondria ROS production.

During reperfusion, the interplay between excess reactive oxygen species (ROS) production, mitochondrial Ca(2+) overload, and mitochondrial permeability transition pore (mPTP) opening, as the crucial mechanism of cardiomyocyte injury, remains intriguing. Here, we investigated whether an induction of a partial decrease in mitochondrial membrane potential (DeltaPsi(m)) is an underlying mechanism of protection by anesthetic-induced preconditioning (APC) with isoflurane, specifically addressing the interplay between ROS, Ca(2+), and mPTP opening. The magnitude of APC-induced decrease in DeltaPsi(m) was mimicked with the protonophore 2,4-dinitrophenol (DNP), and the addition of pyruvate was used to reverse APC- and DNP-induced decrease in DeltaPsi(m). In cardiomyocytes, DeltaPsi(m), ROS, mPTP opening, and cytosolic and mitochondrial Ca(2+) were measured using confocal microscope, and cardiomyocyte survival was assessed by Trypan blue exclusion. In isolated cardiac mitochondria, antimycin A-induced ROS production and Ca(2+) uptake were determined spectrofluorometrically. In cells exposed to oxidative stress, APC and DNP increased cell survival, delayed mPTP opening, and attenuated ROS production, which was reversed by mitochondrial repolarization with pyruvate. In isolated mitochondria, depolarization by APC and DNP attenuated ROS production, but not Ca(2+) uptake. However, in stressed cardiomyocytes, a similar decrease in DeltaPsi(m) attenuated both cytosolic and mitochondrial Ca(2+) accumulation. In conclusion, a partial decrease in DeltaPsi(m) underlies cardioprotective effects of APC by attenuating excess ROS production, resulting in a delay in mPTP opening and an increase in cell survival. Such decrease in DeltaPsi(m) primarily attenuates mitochondrial ROS production, with consequential decrease in mitochondrial Ca(2+) uptake.

Mitochondrial dysfunction plays a crucial role in the pathological physiology of polycystic ovary syndrome (PCOS). Mitochondrial quality control system is vital to maintaining mitochondrial function, includes mitochondrial biosynthesis, dynamics and mitophagy. While mitophagy as a specific autophagy, plays an important role in the mitochondrial quality control system and is mediated by some signaling pathways to eliminate the excessive production of reactive oxygen species (ROS), such as hypoxia-inducible factor (HIF)-1α/B-cell lymphoma-2 adenovirus E1B 19kDa interacting protein 3 (BNIP3). Our previous studies have found that excessive production of ROS and the decreased expression of HIF-1α in the ovaries of PCOS rats. Thus, we hypothesized that excessive ROS leads to mitochondrial dysfunction, attenuates HIF-1α/BNIP3-mediated mitophagy in the ovaries of PCOS rats, and further reduces the mitophagic defense. Firstly, the oxidative stress status was detected and found excessive ROS damages ovarian tissue in PCOS rats. Secondly, the marker proteins of mitochondrial biosynthesis/dynamics and amount were examined and found that their expression levels were abnormal, which showed that the abnormal mitochondrial quality control system leads to accumulate the excess or damaged mitochondria in PCOS ovaries. Finally, we detected the HIF-1α/BNIP3 pathway and found HIF-1α-mediated mitophagy is impaired in the ovaries of PCOS rats. Together, these results clearly demonstrated excessive ROS causes mitochondrial dysfunction via the abnormal mitochondrial quality control system, and attenuates HIF-1α/BNIP3-mediated mitophagic defense in the granulosa cells of PCOS rats, which will provide a new direction for further understanding the role of HIF-1α in the molecular mechanism of mitochondrial dysfunction in PCOS ovaries.

Mitochondria play a central role in energy metabolism and continuously adapt through dynamic processes such as fusion and fission. When the balance between these processes is disrupted, it can lead to mitochondrial dysfunction and increased oxidative stress, contributing to the development and progression of various cardiometabolic diseases (CMDs). Their role is crucial in diabetes mellitus (DM), since their dysfunction drives β-cell apoptosis, immune activation, and chronic inflammation through excessive ROS production, worsening endogenous insulin secretion. Moreover, sympathetic nervous system activation and altered dynamics, contribute to hypertension through oxidative stress, impaired mitophagy, endothelial dysfunction, and cardiomyocyte hypertrophy. Furthermore, the role of mitochondria is catalytic in endothelial dysfunction through excessive reactive oxygen species (ROS) production, disrupting the vascular tone, permeability, and apoptosis, while impairing antioxidant defense and promoting inflammatory processes. Mitochondrial oxidative stress, resulting from an imbalance between ROS/Reactive nitrogen species (RNS) imbalance, promotes atherosclerotic alterations and oxidative modification of oxidizing low-density lipoprotein (LDL). Mitochondrial DNA (mtDNA), situated in close proximity to the inner mitochondrial membrane where ROS are generated, is particularly susceptible to oxidative damage. ROS activate redox-sensitive inflammatory signaling pathways, notably the nuclear factor kappa B (NF-κB) pathway, leading to the transcriptional upregulation of proinflammatory cytokines, chemokines, and adhesion molecules. This proinflammatory milieu promotes endothelial activation and monocyte recruitment, thereby perpetuating local inflammation and enhancing atherogenesis. Additionally, mitochondrial disruptions in heart failure promote further ischemic injury and excessive oxidative stress release and impair ATP production and Ca2⁺ dysregulation, contributing to cell death, fibrosis, and decreased cardiac performance. This narrative review aims to investigate the intricate relationship between mitochondrial dysfunction and CMDs.

Negative plant–plant interactions through the release of allelochemicals via leaching, decomposition of residues in soil, volatilization and exudation are well established. We aimed to characterise the allelopathic potential of Chrysanthemoides monilifera subsp. monilifera (boneseed) in terms of volatilization and exudation. A series of bioassays compared dose–response to volatilization impacts of boneseed organs on model species Lactuca sativa and associated native Acacia mearnsii with particular reference to investigating physiological and biochemical interference through excessive reactive oxygen species (ROS) production. The impact of boneseed exudates on native Xerochrysum bracteatum and A. mearnsii were investigated in greenhouse. We found significant dose–response impacts of boneseed volatilization in the order of root > leaf > stem on biometric parameters of both of the test species with more significant impact on L. sativa while impact on germination indices was negligible. Hydrogen peroxide, lipid peroxidation and electrolyte leakage in the test species seedlings was increased with increasing doses of boneseed organs, suggesting cellular fragmentation, and a potential mechanism of allelopathic impact through excessive ROS production. Boneseed exudates killed X. bracteatum and inhibited growth parameters of A. mearnsii significantly which was partially reduced by activated carbon treatments. The increase of free proline in A. mearnsii and phenolics in soil, and decrease of soil dehydrogenase activities indicated that boneseed led to a stressed condition in the neighboring species. Our findings help to explain the mechanism of invasion by boneseed and emphasize the importance of mitigating the effects of allelopathy by boneseed to protect native and crop species.

Antibody-mediated cell killing has significantly facilitated the elimination of undesired cells in therapeutic applications. Besides the well-known Fc-dependent mechanisms, pathways of antibody-induced apoptosis were also extensively studied. However, with fewer studies reporting the ability of antibodies to evoke an alternative form of programmed cell death, oncosis, the molecular mechanism of antibody-mediated oncosis remains underinvestigated. In this study, a monoclonal antibody (mAb), TAG-A1 (A1), was generated to selectively kill residual undifferentiated human embryonic stem cells (hESC) so as to prevent teratoma formation upon transplantation of hESC-derived products. We revealed that A1 induces hESC death via oncosis. Aided with high-resolution scanning electron microscopy (SEM), we uncovered nanoscale morphological changes in A1-induced hESC oncosis, as well as A1 distribution on hESC surface. A1 induces hESC oncosis via binding-initiated signaling cascade, most likely by ligating receptors on surface microvilli. The ability to evoke excess reactive oxygen species (ROS) production via the Nox2 isoform of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is critical in the cell death pathway. Excess ROS production occurs downstream of microvilli degradation and homotypic adhesion, but upstream of actin reorganization, plasma membrane damage and mitochondrial membrane permeabilization. To our knowledge, this is the first mechanistic model of mAb-induced oncosis on hESC revealing a previously unrecognized role for NAPDH oxidase-derived ROS in mediating oncotic hESC death. These findings in the cell death pathway may potentially be exploited to improve the efficiency of A1 in eliminating undifferentiated hESC and to provide insights into the study of other mAb-induced cell death.

Sex-dependent phosphorylation of Argonaute 2 reduces the mitochondrial translocation of miR-181c and induces cardioprotection in females

Excessive reactive oxygen species production during acute lung injury (ALI) will aggravate the inflammatory process and endothelial barrier dysfunction. Carnosol is a natural phenolic diterpene with antioxidant and anti-inflammatory properties, but its role in treating sepsis-induced ALI remains unclear. This study aims to explore the protective effects and underlying mechanisms of carnosol in sepsis-induced ALI. C57BL/6 mouse were preconditioned with carnosol for 1 h, then the model of lipopolysaccharide (LPS)-induced sepsis was established. The degree of pulmonary edema, oxidative stress, and inflammation were detected. Endothelial barrier function was evaluated by apoptosis and cell junctions. In vitro, Mito Tracker Green probe, JC-1 staining, and MitoSOX staining were conducted to investigate the effect of carnosol on mitochondria. Finally, we investigated the role of nuclear factor-erythroid 2-related factor (Nrf2)/sirtuin-3 (SIRT3) in carnosol against ALI. Carnosol alleviated LPS-induced pulmonary oxidative stress and inflammation by inhibiting excess mitochondrial reactive oxygen species production and maintaining mitochondrial homeostasis. Furthermore, carnosol also attenuated LPS-induced endothelial cell barrier damage by reducing vascular endothelial cell apoptosis and restoring occludin, ZO-1, and vascular endothelial-Cadherin expression in vitro and in vivo. In addition, carnosol increased Nrf2 nuclear translocation to promote SIRT3 expression. The protective effects of carnosol on ALI were largely abolished by inhibition of Nrf2/SIRT3. Our study has provided the first evidence that the Nrf2/SIRT3 pathway is a protective target of the endothelial barrier in ALI, and carnosol can serve as a potential therapeutic candidate for ALI by utilizing its ability to target this pathway.

Polychlorinated Biphenyl Mixture Aroclor 1254-Induced Oxidative Stress Plays a Role in Dopaminergic Cell Injury

Ulcerative colitis (UC) is a multifactorial inflammatory disease, and increasing evidence has demonstrated that the mechanism of UC pathogenesis is associated with excessive cellular apoptosis and reactive oxygen species (ROS) production. However, their function and molecular mechanisms related to UC remain unknown. In this study, Rab27A mRNA and protein were proven to be overexpressed in intestinal epithelial cells of UC patients and DSS‐induced colitis mice, compared with control (P < 0.05). And Rab27A silencing inhibits inflammatory process in DSS‐induced colitis mice (P < 0.05). Then, it was shown that knockdown of Rab27A suppressed apoptosis and ROS production through modulation of miR‐124‐3p, whereas overexpression of Rab27A promoted apoptosis and ROS production in LPS‑induced colonic cells. In addition, enhanced expression of miR‐124‐3p attenuated apoptosis and ROS production by targeting regulation of STAT3 in LPS‑induced colonic cells. Mechanistically, we found Rab27A reduced the expression and activity of miR‐124‐3p to activate STAT3/RelA signalling pathway and promote apoptosis and ROS production in LPS‑induced colonic cells, whereas overexpression of miR‐124‐3p abrogated these effects of Rab27A. More importantly, animal experiments illustrated that ectopic expression of Rab27A promoted the inflammatory process, whereas overexpression of miR‐124‐3p might interfere with the inflammatory effect in DSS‐induced colitis mice. In summary, Rab27A might modulate the miR‐124‐3p/STAT3/RelA axis to promote apoptosis and ROS production in inflammatory colonic cells, suggesting that Rab27A as a novel therapeutic target for the prevention and treatment of UC patients.

Nonalcoholic Fatty Liver Disease (NAFLD) is a chronic disease characterized by excessive fat accumulation, inflammation and liver dysfunction in the absence of significant alcohol consumption and without any other liver disease. NAFLD is accompanied by mitochondrial dysfunctions such as decreased activity of the enzymes of the electron transport chain (ETC), impaired β‐oxidation of fatty acids, excessive reactive oxygen species (ROS) production and increased lipid peroxidation. These last two processes have been involved in liver inflammation by augmenting the activity of cytokines like TNF‐α, and IL‐6. Mitochondrial dynamics, a process that modulates both mitochondrial morphology and function by events of fusion and fission, also becomes impaired during NAFLD by exacerbating mitochondria fission. Previously, we have reported that avocado oil, a rich source of C18:1, bioactive sterols and antioxidants, attenuates both mitochondrial dysfunctions and oxidative stress during diabetes and hypertension. Therefore, we aimed to test if avocado oil attenuates NAFLD by counteracting the alterations in both cytokines levels and mitochondrial dynamics in rats feed with a diet with high fat and fructose for 4 months. This diet led to hepatic alterations including inflammation, ballooning, necrosis and increased expression of both TNF‐α and IL‐6. Increased levels of ROS production and lipid peroxidation were observed in mitochondria, along with augmented expression of DRP1 and Fis1, two proteins of fission, and decreased levels of fusion proteins Mfn1/2 and OPA1. All these effects were counteracted when avocado oil was supplemented daily after one month of the beginning of the diet up to the end of the experiment. These data suggest that avocado oil ameliorates NAFLD by decreasing inflammation and improving mitochondrial dynamics. Thus, avocado oil may be a nutritional approach to complement pharmacological treatment of NAFLD.Support or Funding InformationThis work was supported by a Coordinación de la Investigación Científica‐UMSNH grant (to CCR)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.