A quirky truth is that the oldest biomarker findings are largely metabolic. These had minimal impact on contemporary thought and research and were largely ignored. They have been rediscovered and validated almost 100 years later, informing our understanding of neurobiology and medical comorbidity and spurring contemporary treatment discovery efforts.

Metabolic dysfunction has been long associated with severe mental illness (SMI), often viewed as a comorbidity to be managed. However, emerging evidence suggests that metabolic dysfunction, particularly at the mitochondrial level, may be a foundational element in the pathophysiology of neuropsychiatric disorders. This commentary expands on the current understanding by exploring the brain energy theory of mental illness, which posits that mitochondrial dysfunction is central to both metabolic and psychiatric conditions. The roles of insulin resistance, chronic stress and environmental factors are highlighted as shared biopsychosocial determinants that contribute to deterioration in both metabolic and mental health. The therapeutic potential of the ketogenic diet is discussed, particularly its ability to improve mitochondrial function and alleviate psychiatric symptoms. This shift in perspective, from viewing metabolic dysfunction as a secondary concern to recognising it as a root cause of SMI, has significant implications for clinical practice and research. By focusing on bioenergetic deficits and mitochondrial health, psychiatry may advance towards more effective, integrated treatment approaches that target the underlying cellular dysfunctions driving both metabolic and mental illnesses.

The incidence of obesity-related glomerulopathy (ORG) is rising worldwide with very limited treatment methods. Paralleled with the gut–kidney axis theory, the beneficial effects of butyrate, one of the short-chain fatty acids (SCFA) produced by gut microbiota, on metabolism and certain kidney diseases have gained growing attention. However, the effects of butyrate on ORG and its underlying mechanism are largely unexplored. In this study, a mice model of ORG was established with a high-fat diet feeding for 16 weeks, and sodium butyrate treatment was initiated at the 8th week. Podocyte injury, oxidative stress and mitochondria function were evaluated in mice kidney and validated in vitro in palmitic acid-treated-mouse podocyte cell lines. Further, the molecular mechanisms of butyrate on podocytes were explored. Compared with controls, sodium butyrate treatment alleviated kidney injuries and renal oxidative stress in high-fat diet-fed mice. In mouse podocyte cell lines, butyrate ameliorated palmitic acid-induced podocyte damage and helped maintain the structure and function of the mitochondria. Moreover, the effects of butyrate on podocytes were mediated via the GPR43-Sirt3 signal pathway, as evidenced by the diminished effects of butyrate with the intervention of GPR43 or Sirt3 inhibitors. In summary, we conclude that butyrate has therapeutic potential for the treatment of ORG. It attenuates high-fat diet-induced ORG and podocyte injuries through the activation of the GPR43-Sirt3 signalling pathway.

Echinostoma miyagawai is a cosmopolitan parasite within the Echinostomatidae and is a cause of human echinostomiasis. Species within the family have been a challenge to disentangle with E. miyagawai being synonyms of several other Echinostoma species. However, complete mitochondrial genomes have been shown to be vital in distinguishing echinostomatid species, but detailed comparisons of not only gene content but also structural features have been limited. Using long range sequencing techniques, the complete mitochondrial genome of E. miyagawai was sequenced and compared to other members of Echinostomatidae. In total 12 protein coding genes, 2 ribosomal RNA genes and 22 transfer RNA genes were identified, as was an extensive noncoding control region (CR), consisting of 2 types of multiple tandem repeat units. Phylogenetic analyses of complete mitochondrial genomes corresponded to previous studies on single mitochondrial genes and nuclear ribosomal nuclear markers confirmed E. miyagawai to be within in the ‘Echinostoma revolutum’ group. The tandem repeat units found in the CR contained promoter sequences containing domains typical of initiation sites for replication and transcription as well as several palindromic regions which were shared between echinostomatid species. The study illustrates not only the utility complete mitogenomes in disentangling the relationship between these parasite species, but also provides some insight into the potential adaptations and other evolutionary processes that may govern the divergence of mitochondrial genomes for the first time in echinostomatids.

Mitochondrial dysfunction is a common feature of brain disorders. Mitochondria play a central role in oxidative phosphorylation; thus changes in energy metabolism in the brain have been reported in conditions such as Alzheimer’s disease, Parkinson’s disease, and stroke. In addition, mitochondria regulate cellular responses associated with neuronal damage such as the production of reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), and apoptosis. Therefore, interventions that aim to protect mitochondria may be effective against brain disorders. Fucoxanthin is a marine carotenoid that has recently gained recognition for its neuroprotective properties. However, the cellular mechanisms of fucoxanthin in brain disorders, particularly its role in mitochondrial function, have not been thoroughly discussed. This review summarises the current literature on the effects of fucoxanthin on oxidative stress, neuroinflammation, and apoptosis using in vitro and in vivo models of brain disorders. We further present the potential mechanisms by which fucoxanthin protects mitochondria, with the objective of developing dietary interventions for a spectrum of brain disorders. Although the studies reviewed are predominantly preclinical studies, they provide important insights into understanding the cellular and molecular functions of fucoxanthin in the brain. Future studies investigating the mechanisms of action and the molecular targets of fucoxanthin are warranted to develop translational approaches to brain disorders.

In vitro maturation of oocytes (IVM) represents an assisted reproductive technique that involves the minimal or absence of ovarian stimulation and is beneficial to specific groups of patients. These may include women with polycystic ovarian syndrome and/or patients who need a fertility preservation option before undergoing gonadotoxic treatment. However, when IVM is applied in cases where it is not recommended, it can be considered as an add-on technique, as described by the ESHRE Guideline Group on Female Fertility Preservation. Interestingly, IVM has not been proven yet to be as effective as conventional IVF in the laboratory, in terms of clinical pregnancy and live birth rates, while concerns have been raised for its long-term safety. As a result, both safety and efficacy of IVM remain still questionable and additional data are needed to draw conclusions.

PARP2, that belongs to the family of ADP-ribosyl transferase enzymes (ART), is a discovery of the millennium, as it was identified in 1999. Although PARP2 was described initially as a DNA repair factor, it is now evident that PARP2 partakes in the regulation or execution of multiple biological processes as inflammation, carcinogenesis and cancer progression, metabolism or oxidative stress-related diseases. Hereby, we review the involvement of PARP2 in these processes with the aim of understanding which processes are specific for PARP2, but not for other members of the ART family. A better understanding of the specific functions of PARP2 in all of these biological processes is crucial for the development of new PARP-centred selective therapies.

Mitochondria are unique organelles to perform critical functions such as energy production, lipid oxidation, calcium homeostasis, and steroid hormone synthesis in eukaryotic cells. The proper functioning of mitochondria is crucial for cellular survival, homeostasis, and bioenergetics. Mitochondrial structure and function are maintained by the mitochondrial quality control system, which consists of the processes of mitochondrial biogenesis, mitochondrial dynamics (fusion/fission), mitophagy, and mitochondrial unfolded protein response UPRMT. Mitochondrial dysfunction and/or damage is associated with the initiation and progression of several human diseases, including neurodegenerative, cardiovascular, age-related diseases, diabetes, and cancer. Environmental stress and contaminants may exacerbate the sensitivity of mitochondria to damage which causes mitochondrial dysfunction. There is growing evidence about the impact of nanoplastics (NPs) and microplastics (MPs) on mitochondrial health and function. MPs/NPs were reported to trigger oxidative stress and reactive oxygen species production, which eventually change mitochondrial membrane potential. MPs/NPs can cross through the biological barriers in the human body and be internalized by the cells, potentially altering mitochondrial dynamics, bioenergetics, and signaling pathways, thus impacting cellular metabolism and function. This review states the effects of MPs/NPs on mitochondrial homeostasis and function as well as on mitochondrial membrane dynamics, mitophagy, and mitochondrial apoptosis are discussed.

This study aimed to investigate the structural and metabolic changes in cumulus cells of underweight women and their effects on oocyte maturation and fertilization. The cytoplasmic ultrastructure was analyzed by electron microscopy, mitochondrial membrane potential by immunofluorescence, and mitochondrial DNA copy number by relative quantitative polymerase chain reaction. The expression of various proteins including the oxidative stress-derived product 4-hydroxynonenal (4-HNE) and autophagy and apoptosis markers such as Vps34, Atg-5, Beclin 1, Lc3-I, II, Bax, and Bcl-2 was assessed and compared between groups. Oocyte maturation and fertilization rates were lower in underweight women (P < 0.05), who presented with cumulus cells showing abnormal mitochondrial morphology and increased cell autophagy. Compared with the mitochondrial DNA copies of the control group, those of the underweight group increased but not significantly. The mitochondrial membrane potential was similar between the groups (P = 0.8). Vps34, Atg-5, Lc3-II, Bax, and Bcl-2 expression and 4-HNE levels were higher in the underweight group compared with the control group (P < 0.01); however, the Bax/Bcl-2 ratio was lower in the underweight group compared with the control group (P = 0.031). Additionally, Beclin 1 protein levels were higher in the underweight group compared with the control group but without statistical significance. In conclusion, malnutrition and other conditions in underweight women may adversely affect ovulation, and the development, and fertilization of oocytes resulting from changes to the intracellular structure of cumulus cells and metabolic processes. These changes may lead to reduced fertility or unsatisfactory reproduction outcomes in women.

The maintenance of a healthy mitochondrial network and the ability to adjust organelle population in response to internal or external stimuli are essential for the function and the survival of eukaryotic cells. Over the last two decades several studies have demonstrated the paramount importance of mitophagy, a selective form of autophagy that removes damaged and/or superfluous organelles, in organismal physiology. Post-mitotic neuronal cells are particularly vulnerable to mitochondrial damage, and mitophagy impairment has emerged as a causative factor in multiple neurodegenerative pathologies, including Alzheimer's disease and Parkinson's disease among others. Although mitochondrial turnover is a multifaceted process, neurons have to tackle additional complications, arising from their pronounced bioenergetic demands and their unique architecture and cellular polarisation that render the degradation of distal organelles challenging. Mounting evidence indicates that despite the functional conservation of mitophagy pathways, the unique features of neuronal physiology have led to the adaptation of compartmentalised solutions, which serve to ensure seamless mitochondrial removal in every part of the cell. In this review, we summarise the current knowledge concerning the molecular mechanisms that mediate mitophagy compartmentalisation and discuss their implications in various human pathologies.

The aim of this study was to assess mitochondrial DNA analysis as a predictor of the pregnancy potential of biopsied preimplantation embryos. The study included 78 blastomeres biopsied from day 4 cleavage stage euploid embryos. The embryo karyotype was confirmed by 24-chromosome preimplantation genetic testing for aneuploidies using the Illumina Next-Generation Sequencing (NGS) system. Mitochondria viability ratios (mtV) were determined from BAM files subjected to the web-based genome-analysis tool Galaxy. From this cohort of patients, 30.4% of patients (n = 34) failed to establish pregnancy. The mean mtV ratio [mean = 1.51 ± 1.25–1.77 (95% CI)] for this group was significantly (P < 0.01) lower compared with the embryo population that resulted in established pregnancies [mean = 2.5 ± 1.82–2.68 (95% CI)]. mtV multiple of mean (MoM) values were similarly significantly (P < 0.01) lower in blastocysts failing to establish pregnancy. At a 0.5 MoM cut-off, the sensitivity of mtV quantitation was 35.3% and specificity was 78.2%. The positive predictive value for an mtV value > 0.5 MoM was 41.4%. This study demonstrates the clinical utility of preimplantation quantification of viable mitochondrial DNA in biopsied blastomeres as a prognosticator of pregnancy potential.

Prenatal glucocorticoid overexposure causes adult metabolic dysfunction in several species but its effects on adult mitochondrial function remain largely unknown. Using respirometry, this study examined mitochondrial substrate metabolism of fetal and adult ovine biceps femoris (BF) and semitendinosus (ST) muscles after cortisol infusion before birth. Physiological increases in fetal cortisol concentrations pre-term induced muscle- and substrate-specific changes in mitochondrial oxidative phosphorylation capacity in adulthood. These changes were accompanied by muscle-specific alterations in protein content, fibre composition and abundance of the mitochondrial electron transfer system (ETS) complexes. In adult ST, respiration using palmitoyl-carnitine and malate was increased after fetal cortisol treatment but not with other substrate combinations. There were also significant increases in protein content and reductions in the abundance of all four ETS complexes, but not ATP synthase, in the ST of adults receiving cortisol prenatally. In adult BF, intrauterine cortisol treatment had no effect on protein content, respiratory rates, ETS complex abundances or ATP synthase. Activity of citrate synthase, a marker of mitochondrial content, was unaffected by intrauterine treatment in both adult muscles. In the ST but not BF, respiratory rates using all substrate combinations were significantly lower in the adults than fetuses, predominantly in the saline-infused controls. The ontogenic and cortisol-induced changes in mitochondrial function were, therefore, more pronounced in the ST than BF muscle. Collectively, the results show that fetal cortisol overexposure programmes mitochondrial substrate metabolism in specific adult muscles with potential consequences for adult metabolism and energetics.

Early-life malnutrition plays a critical role in foetal development and predisposes to metabolic diseases later in life, according to the concept of ‘developmental programming’. Different types of early nutritional imbalance, including undernutrition, overnutrition and micronutrient deficiency, have been related to long-term metabolic disorders. Accumulating evidence has demonstrated that disturbances in nutrition during the period of preconception, pregnancy and primary infancy can affect mitochondrial function and epigenetic mechanisms. Moreover, even though multiple mechanisms underlying non-alcoholic fatty liver disease (NAFLD) have been described, in the past years, special attention has been given to mitochondrial dysfunction and epigenetic alterations. Mitochondria play a key role in cellular metabolic functions. Dysfunctional mitochondria contribute to oxidative stress, insulin resistance and inflammation. Epigenetic mechanisms have been related to alterations in genes involved in lipid metabolism, fibrogenesis, inflammation and tumorigenesis. In accordance, studies have reported that mitochondrial dysfunction and epigenetics linked to early-life nutrition can be important contributing factors in the pathogenesis of NAFLD. In this review, we summarise the current understanding of the interplay between mitochondrial dysfunction, epigenetics and nutrition during early life, which is relevant to developmental programming of NAFLD.