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Organismal ageing is accompanied by progressive loss of cellular function and systemic deterioration of multiple tissues, leading to impaired function and increased vulnerability to death. Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases. A growing body of evidence suggests that ageing and age-related diseases are tightly related to an energy supply and demand imbalance, which might be alleviated by a variety of interventions, including physical activity and calorie restriction, as well as naturally occurring molecules targeting conserved longevity pathways. Here, we review key historical advances and progress from the past few years in our understanding of the role of mitochondria in ageing and age-related metabolic diseases. We also highlight emerging scientific innovations using mitochondria-targeted therapeutic approaches.This Review discusses the role of mitochondria in metabolism and how mitochondria contribute to age-related metabolic diseases. This knowledge might guide us in designing therapies targeting metabolic disorders to extend human health span and lifespan.

Metabolic diseases, such as type 2 diabetes or obesity, are the consequence of the disruption of the organism’s metabolic pathways. The discovery of small non-coding RNAs—microRNAs (miRNAs)—as post-transcriptional gene regulators opened new doors for the development of novel strategies to combat said diseases. The two strands of miR-378a, miR-378a-3p, and miR-378a-5p are encoded in the Ppargc1b gene and have an active role in the regulation of several metabolic pathways such as mitochondrial metabolism and autophagy. Recent studies recognized miR-378a as an important regulator of energy and glucose homeostasis, highlighting it as a potential target for the improvement of metabolic dysregulation. In the present review, the current knowledge on miR-378a will be discussed with a particular emphasis on its biological functions and mechanisms of action in metabolism, mitochondria, and autophagy.

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu 230 , located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.

Liver ischemia-reperfusion injury (LIRI) is a major cause of the development of complications in different clinical settings such as liver resection and liver transplantation. Damage arising from LIRI is a major risk factor for early graft rejection and is associated with higher morbidity and mortality after surgery. Although the mechanisms leading to the injury of parenchymal and non-parenchymal liver cells are not yet fully understood, mitochondrial dysfunction is recognized as a hallmark of LIRI that exacerbates cellular injury. Mitochondria play a major role in glucose metabolism, energy production, reactive oxygen species (ROS) signaling, calcium homeostasis and cell death. The diverse roles of mitochondria make it essential to preserve mitochondrial health in order to maintain cellular activity and liver integrity during liver ischemia/reperfusion (I/R). A growing body of studies suggest that protecting mitochondria by regulating mitochondrial biogenesis, fission/fusion and mitophagy during liver I/R ameliorates LIRI. Targeting mitochondria in conditions that exacerbate mitochondrial dysfunction, such as steatosis and aging, has been successful in decreasing their susceptibility to LIRI. Studying mitochondrial dysfunction will help understand the underlying mechanisms of cellular damage during LIRI which is important for the development of new therapeutic strategies aimed at improving patient outcomes. In this review, we highlight the progress made in recent years regarding the role of mitochondria in liver I/R and discuss the impact of liver conditions on LIRI.

Reactive oxygen species (ROS) are important second messengers in many metabolic processes and signaling pathways. Disruption of the balance between ROS generation and antioxidant defenses results in the overproduction of ROS and subsequent oxidative damage to biomolecules and cellular components that disturb cellular function. Oxidative stress contributes to the initiation and progression of many liver pathologies such as ischemia-reperfusion injury (LIRI), non-alcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC). Therefore, controlling ROS production is an attractive therapeutic strategy in relation to their treatment. In recent years, increasing evidence has supported the therapeutic effects of polyphenols on liver injury via the regulation of ROS levels. In the current review, we summarize the effects of polyphenols, such as quercetin, resveratrol, and curcumin, on oxidative damage during conditions that induce liver injury, such as LIRI, NAFLD, and HCC.

Diabetic retinopathy (DR), a major complication of diabetes, is driven by chronic inflammation in which retinal microglial cells play a central role. The Hippo pathway kinases NDR1/2 regulate macrophage function, but their role in microglia and DR remain unknown. This study investigates the function of the NDR2 kinase in microglial cells under high-glucose (HG) conditions. Using CRISPR-Cas9, we partially knocked out the Ndr2/Stk38l gene in BV-2 mouse microglial cells and analyzed metabolic activity, phagocytosis, migration, and cytokine release. We confirmed NDR2 expression in microglia and observed increased levels under HG, suggesting a role in hyperglycemia-induced stress. Ndr2/Stk38l (hereafter referred to as Ndr2) downregulation impaired mitochondrial respiration and reduced metabolic flexibility, indicating defective stress adaptation. Functionally, microglia with a partial downregulation of Ndr2 displayed reduced phagocytic and migratory capacity—both dependent on cytoskeletal dynamics. Moreover, Ndr2 downregulation altered the secretory profile, elevating pro-inflammatory cytokines (IL-6, TNF, IL-17, IL-12p70) even under normal glucose levels. These findings identify NDR2 protein kinase as a key regulator of microglial metabolism and inflammatory behavior under diabetic conditions. By modulating immune and metabolic responses, NDR2 may contribute to the neuroinflammatory processes underlying DR. Targeting NDR2 function in microglia may offer novel therapeutic strategies to mitigate retinal inflammation and progression of DR.

Hepatic ischemia reperfusion injury (HIRI) is a major hurdle in many clinical scenarios, including liver resection and transplantation. Various studies and countless surgical events have led to the observation of a strong correlation between HIRI induced by liver transplantation and early allograft-dysfunction development. The detrimental impact of HIRI has driven the pursuit of new ways to alleviate its adverse effects. At the core of HIRI lies mitochondrial dysfunction. Various studies, from both animal models and in clinical settings, have clearly shown that mitochondrial function is severely hampered by HIRI and that its preservation or restoration is a key indicator of successful organ recovery. Several strategies have been thus implemented throughout the years, targeting mitochondrial function. This work briefly discusses some the most utilized approaches, ranging from surgical practices to pharmacological interventions and highlights how novel strategies can be investigated and implemented by intricately discussing the way mitochondrial function is affected by HIRI.

The paramount importance of a healthy diet in the prevention of type 2 diabetes is now well recognized. Blueberries (BBs) have been described as attractive functional fruits for this purpose. This study aimed to elucidate the cellular and molecular mechanisms pertaining to the protective impact of blueberry juice (BJ) on prediabetes. Using a hypercaloric diet-induced prediabetic rat model, we evaluated the effects of BJ on glucose, insulin, and lipid profiles; gut microbiota composition; intestinal barrier integrity; and metabolic endotoxemia, as well as on hepatic metabolic surrogates, including several related to mitochondria bioenergetics. BJ supplementation for 14 weeks counteracted diet-evoked metabolic deregulation, improving glucose tolerance, insulin sensitivity, and hypertriglyceridemia, along with systemic and hepatic antioxidant properties, without a significant impact on the gut microbiota composition and related mechanisms. In addition, BJ treatment effectively alleviated hepatic steatosis and mitochondrial dysfunction observed in the prediabetic animals, as suggested by the amelioration of bioenergetics parameters and key targets of inflammation, insulin signaling, ketogenesis, and fatty acids oxidation. In conclusion, the beneficial metabolic impact of BJ in prediabetes may be mainly explained by the rescue of hepatic mitochondrial bioenergetics. These findings pave the way to support the use of BJ in prediabetes to prevent diabetes and its complications.

Hepatocellular carcinoma (HCC) represents a global health concern, ranking as the sixth most common malignancy worldwide and the third leading cause of cancer-related mortality. Despite advances in research, the diagnosis and prognosis of such malignancy remain challenging. Alpha-fetoprotein, the current serum biomarker used in the management of HCC, has limited sensitivity and specificity, making early detection and effective management more difficult. Thus, new management approaches in diagnosis and prognosis are needed to improve the outcome and survival of HCC patients. SNHG1 is a long noncoding RNA mainly expressed in the cell and cytoplasm of cells and is consistently upregulated in tissues and cell lines of HCC, where it acts as an important regulator of various processes: modulation of p53 activity, sponging of microRNAs with consequent upregulation of their target mRNAs, regulation of fatty acid, iron and glucose metabolism, and interaction with immune cells. The deregulation of these processes results in abnormal cell division, angiogenesis, and apoptosis, thus promoting various aspects of tumorigenesis, including proliferation, invasion, and migration of cells. Clinically, a higher expression of SNHG1 predicts poorer clinical outcomes by significantly correlating with bigger, less differentiated, and more aggressive tumors, more advanced disease stages, and lower overall survival in HCC patients. This article comprehensively summarizes the current understanding of the multifaceted roles of SNHG1 in the pathogenesis of HCC, while also highlighting its clinicopathological correlations, therefore concluding that it has potential as a biomarker in HCC diagnosis and prognosis.

Pharmacological conditioning is a protective strategy against ischemia/reperfusion injury, which occurs during liver resection and transplantation. Polyethylene glycols have shown multiple benefits in cell and organ preservation, including antioxidant capacity, edema prevention and membrane stabilization. Recently, polyethylene glycol 35 kDa (PEG35) preconditioning resulted in decreased hepatic injury and protected the mitochondria in a rat model of cold ischemia. Thus, the study aimed to decipher the mechanisms underlying PEG35 preconditioning-induced protection against ischemia/reperfusion injury. A hypoxia/reoxygenation model using HepG2 cells was established to evaluate the effects of PEG35 preconditioning. Several parameters were assessed, including cell viability, mitochondrial membrane potential, ROS production, ATP levels, protein content and gene expression to investigate autophagy, mitochondrial biogenesis and dynamics. PEG35 preconditioning preserved the mitochondrial function by decreasing the excessive production of ROS and subsequent ATP depletion, as well as by recovering the membrane potential. Furthermore, PEG35 increased levels of autophagy-related proteins and the expression of genes involved in mitochondrial biogenesis and fusion. In conclusion, PEG35 preconditioning effectively ameliorates hepatic hypoxia/reoxygenation injury through the enhancement of autophagy and mitochondrial quality control. Therefore, PEG35 could be useful as a potential pharmacological tool for attenuating hepatic ischemia/reperfusion injury in clinical practice.