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Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.

Fishes’ skeletal muscles are crucial for swimming and are differentiated into slow-twitch muscles (SM) and fast-twitch muscles (FM) based on physiological and metabolic properties. Consequently, mitochondrial characteristics (number and morphology) adapt to each fiber type’s specific functional needs. However, the mechanisms governing mitochondrial adaptation to the specific bioenergetic requirements of each fiber type in teleosts remain unclear. To address this knowledge gap, we investigated the mitochondrial differences and mitochondrial homeostasis status (including biogenesis, autophagy, fission, and fusion) between SM and FM in teleosts using Takifugu rubripes as a representative model. Our findings reveal that SM mitochondria are more numerous and larger compared to FM. To adapt to the increased mitochondrial number and size, SM exhibit elevated mitochondrial biogenesis and dynamics (fission/fusion), yet show no differences in mitochondrial autophagy. Our study provides insights into the adaptive mechanisms shaping mitochondrial characteristics in teleost muscles. The abundance and elongation of mitochondria in SM are maintained through elevated mitochondrial biogenesis, fusion, and fission, suggesting an adaptive response to fulfill the bioenergetic demands of SM that rely extensively on OXPHOS in teleosts. Our findings enhance our understanding of mitochondrial adaptations in diverse muscle types among teleosts and shed light on the evolutionary strategies of bioenergetics in fishes.

Cells have the ability to adapt to stressful environments as a part of their evolution. Physical exercise induces an increase of a demand for energy that must be met by mitochondria as the main (ATP) provider. However, this process leads to the increase of free radicals and the so-called reactive oxygen species (ROS), which are necessary for the maintenance of cell signaling and homeostasis. In addition, mitochondrial biogenesis is influenced by exercise in continuous crosstalk between the mitochondria and the nuclear genome. Excessive workloads may induce severe mitochondrial stress, resulting in oxidative damage. In this regard, the objective of this work was to provide a general overview of the molecular mechanisms involved in mitochondrial adaptation during exercise and to understand if some nutrients such as antioxidants may be implicated in blunt adaptation and/or an impact on the performance of exercise by different means.

Autophagy and mitophagy are important for training-inducible muscle adaptations, yet it remains unclear how these systems are regulated throughout the adaptation process. Here, we studied autophagic and mitophagic flux in the skeletal muscles of Sprague–Dawley rats (300–500 g) exposed to chronic contractile activity (CCA; 3 h/day, 9 V, 10 Hz continuous, 0.1 ms pulse duration) for 1, 2, 5, and 7 days (N = 6–8/group). In order to determine the flux rates, colchicine (COL; 0.4 mg/ml/kg) was injected 48 h before tissue collection, and we evaluated differences of autophagosomal protein abundances (LC3-II and p62) between colchicine- and saline-injected animals. We confirmed that CCA resulted in mitochondrial adaptations, including improved state 3 respiration as early as day 1 in permeabilized muscle fibers, as well significant increases in mitochondrial respiratory capacity and marker proteins in IMF mitochondria by day 7. Mitophagic and autophagic flux (LC3-II and p62) were significantly decreased in skeletal muscle following 7 days of CCA. Notably, the mitophagic system seemed to be downregulated prior (day 3–5) to changes in autophagic flux (day 7), suggesting enhanced sensitivity of mitophagy compared to autophagy with chronic muscle contraction. Although we detected no significant change in the nuclear translocation of TFEB, a regulator of lysosomal biogenesis, CCA increased total TFEB protein, as well as LAMP1, in skeletal muscle. Thus, chronic muscle activity reduces mitophagy in parallel with improved mitochondrial function, and this is supported by enhanced lysosomal degradation capacity.

Non-alcoholic fatty liver disease (NAFLD) is a global pandemic affecting 25% of the world’s population and is a serious health and economic concern worldwide. NAFLD is mainly the result of unhealthy dietary habits combined with sedentary lifestyle, although some genetic contributions to NAFLD have been documented. NAFLD is characterized by the excessive accumulation of triglycerides (TGs) in hepatocytes and encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL) to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although the molecular mechanisms that cause the progression of steatosis to severe liver damage are not fully understood, metabolic-dysfunction-associated fatty liver disease is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Mitochondria are highly dynamic organelles that undergo functional and structural adaptations to meet the metabolic requirements of the cell. Alterations in nutrient availability or cellular energy needs can modify mitochondria formation through biogenesis or the opposite processes of fission and fusion and fragmentation. In NAFL, simple steatosis can be seen as an adaptive response to storing lipotoxic free fatty acids (FFAs) as inert TGs due to chronic perturbation in lipid metabolism and lipotoxic insults. However, when liver hepatocytes’ adaptive mechanisms are overburdened, lipotoxicity occurs, contributing to reactive oxygen species (ROS) formation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Impaired mitochondrial fatty acid oxidation, reduction in mitochondrial quality, and disrupted mitochondrial function are associated with a decrease in the energy levels and impaired redox balance and negatively affect mitochondria hepatocyte tolerance towards damaging hits. However, the sequence of events underlying mitochondrial failure from steatosis to hepatocarcinoma is still yet to be fully clarified. This review provides an overview of our understanding of mitochondrial adaptation in initial NAFLD stages and highlights how hepatic mitochondrial dysfunction and heterogeneity contribute to disease pathophysiology progression, from steatosis to hepatocellular carcinoma. Improving our understanding of different aspects of hepatocytes’ mitochondrial physiology in the context of disease development and progression is crucial to improving diagnosis, management, and therapy of NAFLD/NASH.

Diabetic retinopathy (DR) is the most common complication that develops in patients with diabetes mellitus (DM) and is the leading cause of blindness worldwide. Fortunately, sight-threatening forms of DR develop only after several decades of DM. This well-documented resilience to DR suggests that the retina is capable of protecting itself from DM-related damage and also that accumulation of such damage occurs only after deterioration of this resilience. Despite the enormous translational significance of this phenomenon, very little is known regarding the nature of resilience to DR. Rodent models of DR have been used extensively to study the nature of the DM-induced damage, i.e., cardinal features of DR. Many of these same animal models can be used to investigate resilience because DR is delayed from the onset of DM by several weeks or months. The purpose of this review is to provide a comprehensive overview of the literature describing the use of rodent models of DR in type-1 and type-2 diabetic animals, which most clearly document the delay between the onset of DM and the appearance of DR. These readily available experimental settings can be used to advance our current understanding of resilience to DR and thereby identify biomarkers and targets for novel, prevention-based approaches to manage patients at risk for developing DR.

Endurance training camps are well established in elite sports, but one-week camps for recreational endurance athletes have recently gained popularity despite limited scientific evidence. This study investigated the effects of a one-week endurance training camp on body composition, endurance performance, and markers of metabolic stress and mitochondrial adaptation in recreational athletes. Female and male endurance athletes (≥18 years) participated in a professionally guided one-week endurance training camp. Assessments included body composition, running diagnostics, sleep-quality/recovery-stress questionnaires, nutrition/energy balance diaries, blood profiling, and mitochondrial biogenesis markers. Measurements were conducted before (pre), during (camp), and after the camp (post). A total of 35 participants (18 male/17 female) were included. Body mass and body fat decreased from pre- to post-camp. Lactate concentrations at threshold levels changed, while velocities at fixed lactate concentrations and maximal oxygen uptake did not significantly improve. Post-camp, lactate dehydrogenase, klotho, and vitamin D increased, whereas interferon-γ, kynurenine, cortisol, creatinine, and ferritin decreased. Plasma mitochondrial and nuclear DNA abundance, as well as PGC1-α expression, increased, while vascular endothelial growth factor decreased. A one-week endurance training camp in a holiday-like setting induces measurable physiological, metabolic, and mitochondrial adaptations in recreational athletes and is associated with reduced systemic and psychological stress. However, the concurrent increase in muscle- and cell-stress markers indicates a substantial physiological load.

Dynamin-related protein 1 (Drp1) is essential for mitochondrial dynamics in skeletal muscle, particularly in regulating fission, mitophagy, and maintaining mitochondrial function. Exercise is crucial for sustaining muscle function, promoting mitochondrial adaptations that enhance energy metabolism and oxidative capacity in skeletal muscle. In this Review, we discuss the role of Drp1 in exercise-induced mitochondrial adaptations and its potential implications for skeletal muscle health. We first address the evidence that Drp1 activity must be maintained within a narrow physiological range. Both Drp1 deficiency and overabundance provoke muscle atrophy and dysfunction, establishing a Goldilocks principle for mitochondrial fission. We then examine the multi-layered post-translational modification code that governs Drp1 activity, including canonical phosphorylation, redox-sensing modifications, and the receptor selectivity model that may specify distinct fission programs. A three-stage model of exercise-induced mitochondrial adaptation is presented, describing how Drp1 activity is temporally orchestrated from acute fragmentation through short-term remodeling to long-term network optimization, and how these morphological transitions govern substrate metabolism and determine exercise performance. The pathological consequences of Drp1 dysregulation are examined in metabolic disease, where Drp1 is chronically hyperactivated, and in aging, where Drp1 activity is deficient. Finally, we analyze the ROS-Drp1 signaling axis as the mechanistic basis for the bidirectional regulation of Drp1 by exercise. Moderate exercise-induced ROS production activates Nrf2 and AMPK signaling, which suppress excessive fission in metabolic disease while restoring insufficient fission in aging, thereby moving Drp1 activity toward the physiological Goldilocks zone in both contexts. This context-dependent, bidirectional regulation distinguishes exercise from pharmacological inhibitors and identifies the ROS-Drp1 axis as a therapeutic target for conditions at opposite ends of the Drp1 activity continuum, such as sarcopenia and type 2 diabetes.

Objective Intriguingly, hyperinsulinemia, and hyperglycemia can predispose insulin resistance, obesity, and type 2 diabetes, leading to metabolic disturbances. Conversely, physical exercise stimulates skeletal muscle glucose uptake, improving whole-body glucose homeostasis. Therefore, we investigated the impact of short-term physical activity in a mouse model ( Slc2a4 +/− ) that spontaneously develops hyperinsulinemia and hyperglycemia even when fed on a chow diet. Methods Slc2a4 +/− mice were used, that performed 5 days of endurance or strength exercise training. Further analysis included physiological tests (GTT and ITT), skeletal muscle glucose uptake, skeletal muscle RNA-sequencing, mitochondrial function, and experiments with C2C12 cell line. Results When Slc2a4 +/− mice were submitted to the endurance or strength training protocol, improvements were observed in the skeletal muscle glucose uptake and glucose metabolism, associated with broad transcriptomic modulation, that was, in part, related to mitochondrial adaptations. The endurance training, but not the strength protocol, was effective in improving skeletal muscle mitochondrial activity and unfolded protein response markers (UPRmt). Moreover, experiments with C2C12 cells indicated that insulin or glucose levels could contribute to these mitochondrial adaptations in skeletal muscle. Conclusions Both short-term exercise protocols were efficient in whole-body glucose homeostasis and insulin resistance. While endurance exercise plays an important role in transcriptome and mitochondrial activity, strength exercise mostly affects post-translational mechanisms and protein synthesis in skeletal muscle. Thus, the performance of both types of physical exercise proved to be a very effective way to mitigate the impacts of hyperglycemia and hyperinsulinemia in the Slc2a4 +/− mouse model.

Exercise frequently alters the metabolic processes of oxidative metabolism in athletes, including exposure to extreme reactive oxygen species impairing exercise performance. Therefore, both researchers and athletes have been consistently investigating the possible strategies to improve metabolic adaptations to exercise-induced oxidative stress. N-acetylcysteine (NAC) has been applied as a therapeutic agent in treating many diseases in humans due to its precursory role in the production of hepatic glutathione, a natural antioxidant. Several studies have investigated NAC’s possible therapeutic role in oxidative metabolism and adaptive response to exercise in the athletic population. However, still conflicting questions regarding NAC supplementation need to be clarified. This narrative review aims to re-evaluate the metabolic effects of NAC on exercise-induced oxidative stress and adaptive response developed by athletes against the exercise, especially mitohormetic and sarcohormetic response.