Recent evidence indicates that the SARS-CoV-2 spike protein affects mitochondria with a cell type-dependent outcome. We elucidate the effect of the SARS-CoV-2 receptor binding domain (RBD) on the mitochondrial network and cristae morphology, oxygen consumption, mitoROS production, and inflammatory cytokine expression in cultured human lung microvascular (HLMVECs), coronary artery endothelial (HCAECs), and bronchial epithelial cells (HBECs). Live Mito Orange staining, STED microscopy, and Fiji MiNa analysis were used for mitochondrial cristae and network morphometry; an Agilent XFp analyser for mitochondrial/glycolytic activity; MitoSOX fluorescence for mitochondrial ROS; and qRT-PCR plus Luminex for cytokines. HLMVEC exposure to SARS-CoV-2 RBD resulted in the fragmentation of the mitochondrial network, mitochondrial swelling, increased cristae area, reduced cristae density, and suppressed mitochondrial oxygen consumption and glycolysis. No significant mitochondrial morphology or oxygen consumption changes were observed in HCAECs and HBECs. SARS-CoV-2 RBD induced mitoROS-mediated expression of cytokines GM-CSF and IL-1β in all three investigated cell types, along with IL-8 expression in both endothelial cell types. The findings suggest mitochondrial ROS control SARS-CoV-2 RBD-induced inflammation in HLMVECs, HCAECs, and HBECs, with the mitochondria of HLMVECs being more sensitive to SARS-CoV-2 RBD.

Cardio complications such as arrhythmias and myocardial damage are common in COVID-19 patients. SARS-CoV-2 interacts with the cardiovascular system primarily via the ACE2 receptor. Cardiomyocyte damage in SARS-CoV-2 infection may stem from inflammation, hypoxia–reoxygenation injury, and direct toxicity; however, the precise mechanisms are unclear. In this study, we simulated hypoxia–reoxygenation conditions commonly seen in SARS-CoV-2-infected patients and studied the impact of the SARS-CoV-2 spike protein RBD-epitope on primary rat cardiomyocytes to gain insight into the potential mechanisms underlying COVID-19-related cardiac complications. Cell metabolic activity was evaluated with PrestoBlue^TM. Gene expression of proinflammatory markers was measured by qRT-PCR and their secretion was quantified by Luminex assay. Cardiomyocyte contractility was analysed using the Myocyter plugin of ImageJ. Mitochondrial respiration was determined through Seahorse Mito Stress Test. In hypoxia–reoxygenation conditions, treatment of the SARS-CoV-2 spike RBD-epitope reduced the metabolic activity of primary cardiomyocytes, upregulated Il1β and Cxcl1 expression, and elevated GM-CSF and CCL2 cytokines secretion. Contraction time increased, while amplitude and beating frequency decreased. Acute treatment with a virus RBD-epitope inhibited mitochondrial respiration and lowered ATP production. Under ischaemia-reperfusion, the SARS-CoV-2 RBD-epitope induces cardiomyocyte injury linked to impaired mitochondrial activity.

Mitochondrial structural and functional changes accompany psoriasis, yet the mitochondrial response to psoriatic inflammation in keratinocytes and fibroblasts remains unexplored. In this study, we investigated the effect of psoriasis‐like inflammation (PLI) induced by a cytokine cocktail (interleukin (IL)‐17A, IL‐22 and tumour necrosis factor (TNF)‐α) on mitochondrial network morphology and function in cultured keratinocytes (HaCaT) and fibroblasts (BJ‐5ta). In both cell types, PLI triggered the expression of psoriasis‐related Elafin and high amounts of cytokines (IL‐1, IL‐6), interferons (IFN‐α, IFN‐β, IFN‐γ), and chemokines (C‐C motif chemokine 5 (CCL5) and IL‐8), accompanied by increased mitochondrial membrane potential, reactive oxygen species (ROS) production, respiration suppression, network fragmentation, swelling and cristae disassembly. Stimulated emission depletion (STED) nanoscopy revealed the disappearance of mitochondrial cristae in response to PLI, with the process starting more quickly and being more pronounced in keratinocytes than in fibroblasts. These findings highlight cell‐specific mitochondrial responses to psoriatic inflammation, guiding future investigations towards new pharmacological targets for managing psoriasis.

Mitochondrial structural and functional changes accompany psoriasis, yet the mitochondrial response to psoriatic inflammation in keratinocytes and fibroblasts remains unexplored. In this study, we investigated the effect of psoriasis-like inflammation (PLI) induced by a cytokine cocktail (interleukin (IL)-17A, IL-22 and tumour necrosis factor (TNF)-α) on mitochondrial network morphology and function in cultured keratinocytes (HaCaT) and fibroblasts (BJ-5ta). In both cell types, PLI triggered expression of psoriasis-related Elafin and high amounts of cytokines (IL-1, IL-6), interferons (IFN-α, IFN-β, IFN-γ) and chemokines (C-C motif chemokine 5 (CCL5) and IL-8), accompanied by increased mitochondrial membrane potential, reactive oxygen species (ROS) production, respiration suppression, network fragmentation, swelling, and cristae disassembly. Stimulated emission depletion (STED) nanoscopy revealed the disappearance of mitochondrial cristae in response to PLI, with the process starting more quickly and being more pronounced in keratinocytes than in fibroblasts. These findings highlight cell-specific mitochondrial responses to psoriatic inflammation, guiding future investigations towards new pharmacological targets for managing psoriasis.

Mitochondrial dysfunction, particularly excessive fission, has been implicated in inflammatory signalling in skin diseases such as psoriasis and atopic dermatitis (AD). Current systemic treatments, while effective, are often associated with adverse effects, variable patient responses and high costs. Plant extracts have shown notable anti-inflammatory properties; however, their therapeutic potential is limited due to low penetration and poor bioavailability. Thus, plant-derived nanovesicles (PDNVs) have emerged as an alternative delivery platform, offering bioactive cargo with improved skin penetration and low immunogenic potential. Melissa officinalis L. (Lemon Balm, LB) extracts have demonstrated beneficial effects in inflammatory skin conditions; however, the potential of LB-NVs to modulate skin cell function and cellular energetics in inflammatory conditions remains unexplored. Thus, this study investigated the effects of LB-NVs on mitochondrial function and structure in human skin fibroblasts exposed to a cytokine cocktail (IL-22, IL-17A, TNF-α) to induce a pro-inflammatory state (PInfS). LB-NVs rescued cells from inflammatory metabolic reprogramming by restoring mitochondrial respiration and preventing elevated glycolysis induced by PinfS. Additionally, they reduced mitochondrial fragmentation by regulating the activation of Drp1 and lowered the total p38 MAPK level. Lastly, LB-NVs suppressed IL-4 and IL-13, which are central to AD pathogenesis, and reduced IL-18, a cytokine that commonly increases with disease activity. These findings, for the first time, demonstrate the ability of PDNVs to directly target mitochondrial functions and modulate inflammation, positioning LB-NVs as a highly promising strategy for treating chronic skin inflammation.