Diets with an elevated content of fat, sucrose, or fructose are recognized models of diet-induced metabolic alterations, since they induce metabolic derangements, oxidative stress, and chronic low-grade inflammation associated with local and systemic accumulation of advanced glycation end-products (AGEs). This study used four-week-old C57BL/6 male mice, randomly assigned to three experimental dietary regimens: standard diet (SD), high-fat high-sucrose diet (HFHS), or high fructose diet (HFr), administered for 12 weeks. Plasma, heart, and tibialis anterior (TA) skeletal muscle were assayed for markers of metabolic conditions, inflammation, presence of AGEs, and mitochondrial involvement. The HFHS diet induced a tissue-specific differential response featuring (1) a remarkable adaptation of the heart to HFHS-induced heavy oxidative stress, demonstrated by an increased presence of AGEs and reduced mitochondrial biogenesis, and efficaciously counteracted by a conspicuous increase in mitochondrial fission and PRXIII expression; (2) the absence of TA adaptation to HFHS, revealed by a heavy reduction in mitochondrial biogenesis, not counteracted by an increase in fission and PRXIII expression. HFr-induced mild oxidative stress elicited tissue-specific responses, featuring (1) a decrease in mitochondrial biogenesis in the heart, likely counteracted by a tendency for increased fission and (2) a mild reduction in mitochondrial biogenesis in TA, likely counteracted by a tendency for increased fusion, showing the adaptability of both tissues to the diet.

Mitochondrial oxidative stress and neuroinflammation are involved in the onset and progression of Alzheimer’s disease (AD). Novel reliable, circulating biomarkers related to these processes were searched in cerebrospinal fluid (CSF) and plasma samples. Paired CSF and plasma samples from 20 subjective memory complaints (SMC) subjects, 20 mild cognitive impairment (MCI) due to AD subjects, and 20 Alzheimer’s dementia (ADd) patients were analyzed. Protein amounts of manganese-containing superoxide dismutase 2 (SOD2), cell-free mitochondrial DNA (cf-mtDNA) level, DNase I, and matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) activities were determined. As for SOD2, an MCI male-specific significant increase in both biofluids and an ADd male-specific significant decrease in plasma were found. No significant differences were demonstrated in cf-mtDNA level. An ADd-specific significant increase in plasma DNase I and MMP-2 activities was found. A SMC female-specific significant higher value in CSF MMP-9 activity in comparison to male counterparts was demonstrated. The present results suggest a male patient-specific (MCI and ADd) regulation of SOD2 expression in plasma and support an ADd-specific increase in plasma DNase I and MMP-2 activities. Therefore, the potential of SOD2 amount, DNase I, and MMP-2 activities in plasma as new markers of ADd should be explored. The SMC female-specific high activity of MMP-9 might contribute to AD female-sex bias.

In older adults with reduced physical performance, an increase in the labile iron pool within skeletal muscle is observed. This accumulation is associated with an altered expression of mitochondrial quality control (MQC) markers and increased mitochondrial DNA damage, supporting the hypothesis that impaired MQC contributes to muscle dysfunction during aging. The autophagy–lysosome system plays a critical role in MQC by tagging and engulfing proteins and organelles for degradation in lysosomes. The endolysosomal system is also instrumental in transferrin recycling, which, in turn, regulates cellular iron uptake. In the neuromuscular system, the autophagy–lysosome system supports the structural integrity of neuromuscular junctions, and its dysfunction contributes to muscle atrophy. While MQC was thought to protect against iron-induced cell death, the discovery of ferroptosis, a form of iron-dependent cell death, has highlighted a complex interplay between MQC and iron-inflicted damage. Ferritinophagy, the autophagic degradation of ferritin, if overactivated, can induce ferroptosis. Alternatively, aging may impair ferritinophagy, leading to ferritin accumulation and the release of toxic labile iron under stress, exacerbating oxidative damage and cellular senescence. Physical activity supports muscle health also by preserving mitochondrial quantity and quality and enhancing bioenergetics. However, therapeutic strategies for preventing or reversing physical function decline in aging are still lacking due to the insufficient understanding of the underlying mechanisms. Unveiling how disruptions in iron homeostasis impact muscle quality in older adults may allow for the development of therapeutic strategies targeting iron handling to alleviate age-associated muscle decline.

The coordination of cytoskeletal proteins shapes cell architectures and functions. Age-related changes in cellular mechanical properties have been linked to decreased cellular and tissue dysfunction. Studies have also found a relationship between mitochondrial function and the cytoskeleton. Cytoskeleton inhibitors impact mitochondrial quality and function, including motility and morphology, membrane potential, and respiration. The regulatory properties of the cytoskeleton on mitochondrial functions are involved in the pathogenesis of several diseases. Disassembly of the axon’s cytoskeleton and the release of neurofilament fragments have been documented during neurodegeneration. However, these changes can also be related to mitochondrial impairments, spanning from reduced mitochondrial quality to altered bioenergetics. Herein, we discuss recent research highlighting some of the pathophysiological roles of cytoskeleton disassembly in aging, neurodegeneration, and neuromuscular diseases, with a focus on studies that explored the relationship between intermediate filaments and mitochondrial signaling as relevant contributors to cellular health and disease.

The natural polyphenol resveratrol (RSV) might counteract the skeletal muscle age-related loss of muscle mass and strength/function partly acting on mitochondria. This work analysed the effects of a six-week administration of RSV (50 mg/kg/day) in the oxidative Soleus (Sol) skeletal muscle of old rats (27 months old). RSV effects on key mitochondrial biogenesis proteins led to un unchanged amount of SIRT1 protein and a marked decrease (60 %) in PGC-1 alpha protein. In addition, Peroxyredoxin 3 (PRXIII) protein decreased by 50 %, which on overall suggested the absence of induction of mitochondrial biogenesis by RSV in old Sol. A novel direct correlation between PGC-1 alpha and PRXIII proteins was demonstrated by correlation analysis in RSV and ad -libitum (AL) rats, supporting the reciprocally coordinated expression of the proteins. RSV supplementation led to an unexpected 50 % increase in the frequency of the oxidized base OH8dG in mtDNA. Furthermore, RSV supplementation induced a 50 % increase in the DRP1 protein of mitochondrial dynamics. In both rat groups an inverse correlation between PGC-1 alpha and the frequency of OH8dG as well as an inverse correlation between PRXIII and the frequency of OH8dG were also found, suggestive of a relationship between oxidative damage to mtDNA and mitochondrial biogenesis activity. Such results may indicate that the antioxidant activity of RSV in aged Sol impinged on the oxidative fiber-specific, ROS-mediated, retrograde communication, thereby affecting the expression of SIRT1, PGC-1 alpha and PRXIII, reducing the compensatory responses to the age-related mitochondrial oxidative stress and decline.

Mitochondrial dysfunction is a pivotal contributor to neurodegeneration. Neurons heavily rely on mitochondrial oxidative metabolism and therefore need highly efficient quality control mechanisms, including proteostasis, mitochondrial biogenesis, fusion–fission dynamics, and mitophagy, to sustain bioenergetics and synaptic function. With aging, deterioration of mitochondrial quality control pathways leads to impaired oxidative phosphorylation, excessive reactive oxygen species generation, calcium imbalance, and defective clearance of damaged organelles, ultimately compromising neuronal viability. Pathological protein aggregates, such as α-synuclein in Parkinson’s disease, β-amyloid and tau in Alzheimer’s disease, and misfolded superoxide dismutase 1 and transactive response DNA-binding protein 43 in amyotrophic lateral sclerosis, further aggravate mitochondrial stress, establishing self-perpetuating cycles of neurotoxicity. Such mitochondrial defects underscore mitochondria as a convergent pathogenic hub and a promising therapeutic target for neuroprotection. Intermediate filaments (IFs), traditionally viewed as passive structural elements, have recently gained attention for their roles in cytoplasmic organization, mitochondrial positioning, and energy regulation. Emerging evidence indicates that IF–mitochondria interactions critically influence organelle morphology and function in neurons. This review highlights the multifaceted involvement of mitochondrial dysfunction and IF dynamics in neurodegeneration, emphasizing their potential as targets for novel therapeutic strategies.