Resveratrol impinges on retrograde communication without inducing mitochondrial biogenesis in aged rat soleus muscle.

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-1α 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-1α 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-1α 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-1α and PRXIII, reducing the compensatory responses to the age-related mitochondrial oxidative stress and decline.

Different Effects of High-Fat/High-Sucrose and High-Fructose Diets on Advanced Glycation End-Product Accumulation and on Mitochondrial Involvement in Heart and Skeletal Muscle in Mice.

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.

The Mitochondrial Trigger in an Animal Model of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the leading liver chronic disease featuring hepatic steatosis. Mitochondrial ß-oxidation participates in the derangement of lipid metabolism at the basis of NAFLD, and mitochondrial oxidative stress contributes to the onset of the disease. We evaluated the presence and effects of mitochondrial oxidative stress in the liver from rats fed a high-fat plus fructose (HF-F) diet inducing NAFLD. Supplementation with dehydroepiandrosterone (DHEA), a multitarget antioxidant, was tested for efficacy in delaying NAFLD. A marked mitochondrial oxidative stress was originated by all diets, as demonstrated by the decrease in Superoxide Dismutase 2 (SOD2) and Peroxiredoxin III (PrxIII) amounts. All diets induced a decrease in mitochondrial DNA content and an increase in its oxidative damage. The diets negatively affected mitochondrial biogenesis as shown by decreased peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), mitochondrial transcription factor A (TFAM), and the COX-IV subunit from the cytochrome c oxidase complex. The reduced amounts of Beclin-1 and lipidated LC3 II form of the microtubule-associated protein 1 light chain 3 (LC3) unveiled the diet-related autophagy's decrease. The DHEA supplementation did not prevent the diet-induced changes. These results demonstrate the relevance of mitochondrial oxidative stress and the sequential dysfunction of the organelles in an obesogenic diet animal model of NAFLD.

The Ketogenic Diet Reduces the Harmful Effects of Stress on Gut Mitochondrial Biogenesis in a Rat Model of Irritable Bowel Syndrome.

Functional alterations in irritable bowel syndrome have been associated with defects in bioenergetics and the mitochondrial network. Effects of high fat, adequate-protein, low carbohydrate ketogenic diet (KD) involve oxidative stress, inflammation, mitochondrial function, and biogenesis. The aim was to evaluate the KD efficacy in reducing the effects of stress on gut mitochondria. Newborn Wistar rats were exposed to maternal deprivation to induce IBS in adulthood. Intestinal inflammation (COX-2 and TRL-4); cellular redox status (SOD 1, SOD 2, PrxIII, mtDNA oxidatively modified purines); mitochondrial biogenesis (PPAR-γ, PGC-1α, COX-4, mtDNA content); and autophagy (Beclin-1, LC3 II) were evaluated in the colon of exposed rats fed with KD (IBD-KD) or standard diet (IBS-Std), and in unexposed controls (Ctrl). IBS-Std rats showed dysfunctional mitochondrial biogenesis (PPAR-γ, PGC-1α, COX-4, and mtDNA contents lower than in Ctrl) associated with inflammation and increased oxidative stress (higher levels of COX-2 and TLR-4, SOD 1, SOD 2, PrxIII, and oxidatively modified purines than in Ctrl). Loss of autophagy efficacy appeared from reduced levels of Beclin-1 and LC3 II. Feeding of animals with KD elicited compensatory mechanisms able to reduce inflammation, oxidative stress, restore mitochondrial function, and baseline autophagy, possibly via the upregulation of the PPAR-γ/PGC-1α axis.

The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver.

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.

mtDNA and Mitochondrial Stress Signaling in Human Diseases: A Special Issue.

The completion of the Special Issue dedicated to "mtDNA and mitochondrial stress signaling in human diseases" requests a final overall look to highlight the most valuable findings among the many presented data [...].

Lactobacillus Rhamnosus GG Affects the BDNF System in Brain Samples of Wistar Rats with Pepsin-Trypsin-Digested Gliadin (PTG)-Induced Enteropathy.

Celiac disease (CD) presents as chronic low-grade inflammation of the small intestine often characterized by psychiatric comorbidities. The brain-derived neurotrophic factor (BDNF), which we have shown to be reduced in the serum of CD patients, acts as the bridge between immune activation and the nervous system adaptive response. Since Lactobacillus has been shown to upregulate BDNF, this study aimed to evaluate whether the administration of Lactobacillus rhamnosus GG (L.GG) could positively affect the brain BDNF system in rats mimicking the CD lesions. Data have shown that the administration of pepsin-trypsin digested gliadin (PTG) and L.GG alter the levels of mature BDNF (mBDNF), as evaluated by Western blotting. PTG provoked a reduction of mBDNF compared to controls, and a compensatory increase of its receptor TrkB. L.GG induced a slight positive effect on mBDNF levels under normal conditions, while it was able to rescue the PTG-induced reduced expression of mBDNF. The curative effect of L.GG was finely tuned, accompanied by the reduction of TrkB, probably to avoid the effect of excessive BDNF.

Deletion of OGG1 Results in a Differential Signature of Oxidized Purine Base Damage in mtDNA Regions.

Mitochondrial oxidative stress accumulates with aging and age-related diseases and induces alterations in mitochondrial DNA (mtDNA) content. Since mtDNA qualitative alterations are also associated with aging, repair of mtDNA damage is of great importance. The most relevant form of DNA repair in this context is base excision repair (BER), which removes oxidized bases such as 8-oxoguanine (8-oxoG) and thymine glycol through the action of the mitochondrial isoform of the specific 8-oxoG DNA glycosylase/apurinic or apyrimidinic (AP) lyase (OGG1) or the endonuclease III homolog (NTH1). Mouse strains lacking OGG1 (OGG1-/-) or NTH1 (NTH1-/-) were analyzed for mtDNA alterations. Interestingly, both knockout strains presented a significant increase in mtDNA content, suggestive of a compensatory mtDNA replication. The mtDNA "common deletion" was not detected in either knockout mouse strain, likely because of the young age of the mice. Formamidopyrimidine DNA glycosylase (Fpg)-sensitive sites accumulated in mtDNA from OGG1-/- but not from NTH1-/- mice. Interestingly, the D-loop region was most severely affected by the absence of OGG1, suggesting that this region may be a hotspot for oxidative damage. Thus, we speculate that mtDNA alterations may send a stress message to evoke cell changes through a retrograde mitochondrial-nucleus communication.

Differences in Liver TFAM Binding to mtDNA and mtDNA Damage between Aged and Extremely Aged Rats.

While mitochondrial dysfunction is acknowledged as a major feature of aging, much less is known about the role of mitochondria in extended longevity. Livers from aged (28-month-old) and extremely aged (32-month-old) rats were analyzed for citrate synthase activity, mitochondrial transcription factor A (TFAM) amount, mitochondrial DNA (mtDNA), and 4.8 Kb "common deletion" contents. None of the assayed parameters differed significantly between age groups. TFAM-binding to mtDNA and the incidence of 8-oxo-deoxyguanosine in specific mtDNA regions, encompassing the origins of mtDNA replication (D-loop and Ori-L) and the 16-bp long direct repeat 1 (DR1) of the 4.8 Kb deletion, were determined. A decrease in TFAM binding was unveiled at all regions in extremely aged in comparison with aged rats. Reduced incidence of oxidized purines at all assayed regions was detected in 32-month-old rats compared with the 28-month-old group. A significant positive correlation between the incidence of 8-oxo-deoxoguanosine and TFAM-bound mtDNA was found at D-Loop and Ori-L regions only in 28-month-old rats. The absence of such correlation in 32-month-old rats indicates a different, fine-tuned regulation of TFAM binding in the two age groups and supports the existence of two different paces in aging and extended aging.

An In Vitro Study on Mitochondrial Compensatory Response Induced by Gliadin Peptides in Caco-2 Cells.

Dietary gliadin may show a broad spectrum of toxicity. The interplay between mitochondria and gliadin-induced oxidative stress has not been thoroughly examined in the intestinal epithelium. In this kinetic study, Caco-2 cells were exposed for 24 h to pepsin-trypsin-digested gliadin, alone or in combination with the antioxidant 2,6-di-tbutyl-p-cresol (BHT), and the effects on mitochondrial biogenesis and mtDNA were studied. Cells ability to recover from stress was determined after 24 h and 48 h of incubation in the culture medium. Gliadin-induced oxidative stress evoked a compensatory response. The stressor triggered a rapid and significant increase of Peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) and Peroxiredoxin III (PrxIII) proteins, and mtDNA amount. As for the effects of gliadin on mtDNA integrity, strand breaks, abasic sites, and modified bases were analyzed in three mtDNA regions. D-loop appeared a more fragile target than Ori-L and ND1/ND2. The temporal trend of the damage at D-loop paralleled that of the amount of mtDNA. Overall, a trend toward control values was shown 48 h after gliadin exposure. Finally, BHT was able to counteract the effects of gliadin. Results from this study highlighted the effects of gliadin-induced oxidative stress on mitochondria, providing valuable evidence that might improve the knowledge of the pathophysiology of gluten-related disorders.

Administration of Enalapril Started Late in Life Attenuates Hypertrophy and Oxidative Stress Burden, Increases Mitochondrial Mass, and Modulates Mitochondrial Quality Control Signaling in the Rat Heart.

Mitochondrial dysfunction is a relevant mechanism in cardiac aging. Here, we investigated the effects of late-life enalapril administration at a non-antihypertensive dose on mitochondrial genomic stability, oxidative damage, and mitochondrial quality control (MQC) signaling in the hearts of aged rats. The protein expression of selected mediators (i.e., mitochondrial antioxidant enzymes, energy metabolism, mitochondrial biogenesis, dynamics, and autophagy) was measured in old rats randomly assigned to receive enalapril (n = 8) or placebo (n = 8) from 24 to 27 months of age. We also assessed mitochondrial DNA (mtDNA) content, citrate synthase activity, oxidative lesions to protein and mtDNA (i.e., carbonyls and the abundance of mtDNA4834 deletion), and the mitochondrial transcription factor A (TFAM) binding to specific mtDNA regions. Enalapril attenuated cardiac hypertrophy and oxidative stress-derived damage (mtDNA oxidation, mtDNA4834 deletion, and protein carbonylation), while increasing mitochondrial antioxidant defenses. The binding of mitochondrial transcription factor A to mtDNA regions involved in replication and deletion generation was enhanced following enalapril administration. Increased mitochondrial mass as well as mitochondriogenesis and autophagy signaling were found in enalapril-treated rats. Late-life enalapril administration mitigates age-dependent cardiac hypertrophy and oxidative damage, while increasing mitochondrial mass and modulating MQC signaling. Further analyses are needed to conclusively establish whether enalapril may offer cardioprotection during aging.

Increased TFAM binding to mtDNA damage hot spots is associated with mtDNA loss in aged rat heart.

The well-known age-related mitochondrial dysfunction deeply affects heart because of the tissue's large dependence on mitochondrial ATP provision. Our study revealed in aged rat heart a significant 25% decrease in mtDNA relative content, a significant 29% increase in the 4.8 Kb mtDNA deletion relative content, and a significant inverse correlation between such contents as well as a significant 38% decrease in TFAM protein amount. The TFAM-binding activity to specific mtDNA regions increased at those encompassing the mtDNA replication origins, D-loop and Ori-L. The same mtDNA regions were screened for different kinds of oxidative damage, namely Single Strand Breaks (SSBs), Double Strand Breaks (DSBs), abasic sites (AP sites) and oxidized bases as 7,8-dihydro-8-oxoguanine (8oxoG). A marked increase in the relative content of mtDNA strand damage (SSBs, DSBs and AP sites) was found in the D-loop and Ori-L regions in the aged animals, unveiling for the first time in vivo an age-related, non-stochastic accumulation of oxidative lesions in these two regions that appear as hot spots of mtDNA damage. The use of Formamidopyrimidine glycosylase (Fpg) demonstrated also a significant age-related accumulation of oxidized purines particularly in the D-loop and Ori-L regions. The detected increased binding of TFAM to the mtDNA damage hot spots in aged heart suggests a link between TFAM binding to mtDNA and loss of mitochondrial genome likely through hindrance of repair processes.

The "BIOmarkers associated with Sarcopenia and PHysical frailty in EldeRly pErsons" (BIOSPHERE) study: Rationale, design and methods.

Sarcopenia, the progressive and generalised loss of muscle mass and strength/function, is a major health issue in older adults given its high prevalence and burdensome clinical implications. Over the years, this condition has been endorsed as a marker for discriminating biological from chronological age. However, the absence of a unified operational definition has hampered its full appreciation by healthcare providers, researchers and policy-makers. In addition to this unsolved debate, the complexity of musculoskeletal ageing represents a major challenge to the identification of clinically meaningful biomarkers. Here, we illustrate the advantages of biomarker discovery procedures in muscle ageing based on multivariate methodologies as an alternative approach to traditional single-marker strategies. The rationale, design and methods of the "BIOmarkers associated with Sarcopenia and PHysical frailty in EldeRly pErsons" (BIOSPHERE) study are described as an application of a multi-marker strategy for the development of biomarkers for the newly operationalised Physical Frailty & Sarcopenia condition.

Update on mitochondria and muscle aging: all wrong roads lead to sarcopenia.

Sarcopenia is a well-known geriatric syndrome that has been endorsed over the years as a biomarker allowing for the discrimination, at a clinical level, of biological from chronological age. Multiple candidate mechanisms have been linked to muscle degeneration during sarcopenia. Among them, there is wide consensus on the central role played by the loss of mitochondrial integrity in myocytes, secondary to dysfunctional quality control mechanisms. Indeed, mitochondria establish direct or indirect contacts with other cellular components (e.g. endoplasmic reticulum, peroxisomes, lysosomes/vacuoles) as well as the extracellular environment through the release of several biomolecules. The functional implications of these interactions in the context of muscle physiology and sarcopenia are not yet fully appreciated and represent a promising area of investigation. Here, we present an overview of recent findings concerning the interrelation between mitochondrial quality control processes, inflammation and the metabolic regulation of muscle mass in the pathogenesis of sarcopenia highlighting those pathways that may be exploited for developing preventive and therapeutic interventions against muscle aging.

Circulating Mitochondrial DNA at the Crossroads of Mitochondrial Dysfunction and Inflammation During Aging and Muscle Wasting Disorders.

Mitochondrial structural and functional integrity is maintained through the coordination of several processes (e.g., biogenesis, dynamics, mitophagy), collectively referred to as mitochondrial quality control (MQC). Dysfunctional MQC and inflammation are hallmarks of aging and are involved in the pathogenesis of muscle wasting disorders, including sarcopenia and cachexia. One of the consequences of failing MQC is the release of mitochondria-derived damage-associated molecular patterns (DAMPs). By virtue of their bacterial ancestry, these molecules can trigger an inflammatory response by interacting with receptors similar to those involved in pathogen-associated responses. Mitochondria-derived DAMPs, especially cell-free mitochondrial DNA, have recently been associated with conditions characterized by chronic inflammation, such as aging and degenerative diseases. Yet, their actual implication in the aging process and muscle wasting disorders is at an early stage of investigation. Here, we review the contribution of mitochondria-derived DAMPs to age-related systemic inflammation. We also provide arguments in support of the exploitation of such signaling pathways for the management of muscle wasting conditions.

Does eating less make you live longer and better? An update on calorie restriction.

The complexity of aging is hard to be captured. However, apart from its tissue-specific features, a structural and functional progressive decline of the whole organism that leads to death, often preceded by a phase of chronic morbidity, characterizes the common process of aging. Therefore, the research goal of scientists in the field moved from the search for strategies able to extend longevity to those ensuring healthy aging associated with a longer lifespan referred to as "healthspan". The aging process is plastic and can be tuned by multiple mechanisms including dietary and genetic interventions. To date, the most robust approach, efficient in warding off the cellular markers of aging, is calorie restriction (CR). Here, after a preliminary presentation of the major debate originated by CR, we concisely overviewed the recent results of CR treatment on humans. We also provided an update on the molecular mechanisms involved by CR and the effects on some of the age-associated cellular markers. We finally reviewed a number of tested CR mimetics and concluded with an evaluation of future applications of such dietary approach.

Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia.

Chemotherapy can cause cachexia, which consists of weight loss associated with muscle atrophy. The exact mechanisms underlying this skeletal muscle toxicity are largely unknown and co-therapies to attenuate chemotherapy-induced side effects are lacking. By using a rat model of cisplatin-induced cachexia, we here characterized the mitochondrial homeostasis in tibialis anterior cachectic muscle and evaluated the potential beneficial effects of the growth hormone secretagogues (GHS) hexarelin and JMV2894 in this setting. We found that cisplatin treatment caused a decrease in mitochondrial biogenesis (PGC-1α, NRF-1, TFAM, mtDNA, ND1), mitochondrial mass (Porin and Citrate synthase activity) and fusion index (MFN2, Drp1), together with changes in the expression of autophagy-related genes (AKT/FoxO pathway, Atg1, Beclin1, LC3AII, p62) and enhanced ROS production (PRX III, MnSOD). Importantly, JMV2894 and hexarelin are capable to antagonize this chemotherapy-induced mitochondrial dysfunction. Thus, our findings reveal a key-role played by mitochondria in the mechanism responsible for GHS beneficial effects in skeletal muscle, strongly indicating that targeting mitochondrial dysfunction might be a promising area of research in developing therapeutic strategies to prevent or limit muscle wasting in cachexia.

Fueling Inflamm-Aging through Mitochondrial Dysfunction: Mechanisms and Molecular Targets.

Among the complex determinants of aging, mitochondrial dysfunction has been in the spotlight for a long time. As the hub for many cellular functions, the maintenance of an adequate pool of functional mitochondria is crucial for tissue homeostasis. Their unique role in energy supply makes these organelles essential, especially in those tissues strictly dependent on oxidative metabolism. Mitochondrial quality control (MQC) is ensured by pathways related to protein folding and degradation as well as by processes involving the entire organelle, such as biogenesis, dynamics, and mitophagy. Dysfunctional MQC, oxidative stress and inflammation are hallmarks of senescence and chronic degenerative diseases. One of the consequences of age-related failing MQC and oxidative stress is the release of mitochondria-derived damage-associated molecular patterns (DAMPs). Through their bacterial ancestry, these molecules contribute to mounting an inflammatory response by interacting with receptors similar to those involved in pathogen-associated responses. Mitochondrial DAMPs, especially cell-free mitochondrial DNA, have recently become the subject of intensive research because of their possible involvement in conditions associated with inflammation, such as aging and degenerative diseases. Here, we review the contribution of mitochondrial DAMPs to inflammation and discuss some of the mechanisms at the basis of their generation.

"What makes some rats live so long?" The mitochondrial contribution to longevity through balance of mitochondrial dynamics and mtDNA content.

Extremely interesting for aging research are those individuals able to reach older ages still with functions similar to those of younger counterparts. We examined liver samples from ad libitum-fed old (28-month-old, AL-28) and ad libitum-fed very old (32-month-old, AL-32) rats for a number of markers, relevant for mitochondrial functionality and mitochondrial DNA (mtDNA) content. As for the mtDNA content and the protein amounts of the citrate synthase and the antioxidant peroxiredoxin III there were no significant changes in the AL-32 animals. No significant longevity-related change was found for TFAM amount, but a 50% reduction in the amount of the Lon protease, responsible for turnover of TFAM inside mitochondria, characterized the AL-32 rats. No longevity-related change was observed also for the amounts of the mtDNA repair enzymes OGG1 and APE1, whereas the intra-mitochondrial amount of the cytochrome c protein showed a 50% increase in the AL-32 rats, indicating a likely reduced initiation of the intrinsic apoptotic pathway. Totally unexpected was the doubling of two proteins, very relevant for mitochondrial dynamics, namely MFN2 and DRP1, in the AL-32 rats. This prompted us to the calculation of all individual fusion indexes that grouped together in the AL-32 rats, while in the AL-28 animals were very different. We found a strong positive correlation between the fusion indexes and the respective mtDNA contents in two AL-28 and four AL-32 rats. This supports the idea that the limited prevalence of fusion above a still active fission should have ensured a functional mitochondrial network and should have led to a quite narrow range of high mtDNA contents, likely the best-suitable for extended longevity. Our findings strongly suggest that, among the multiple causes leading to the longevity of the AL-32 rats, the maintenance of an adult-like balance of mitochondrial dynamics seems to be very relevant for the regulation of mtDNA content and functionality.

Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions: Useful insights from aging and calorie restriction studies.

Mitochondrial biogenesis is regulated to adapt mitochondrial population to cell energy demands. Mitochondrial transcription factor A (TFAM) performs several functions for mtDNA and interactions between TFAM and mtDNA participate to regulation of mitochondrial biogenesis. Such interactions are modulated through different mechanisms: regulation of TFAM expression and turnover, modulation of TFAM binding activity to mtDNA through post-translational modifications and differential affinity of TFAM, occurrence of TFAM sliding on mtDNA filaments and of cooperative binding among TFAM molecules, modulation of protein-protein interactions. The tissue-specific regulation of mitochondrial biogenesis in aging and calorie restriction (CR) highlights the relevance of modulation of TFAM-mtDNA interactions.