Showing papers on "Mitochondrial biogenesis published in 2022"

Emerging Role of cAMP/AMPK Signaling

Abstract: The 5′-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a natural energy sensor in mammalian cells that plays a key role in cellular and systemic energy homeostasis. At the cellular level, AMPK supports numerous processes required for energy and redox homeostasis, including mitochondrial biogenesis, autophagy, and glucose and lipid metabolism. Thus, understanding the pathways regulating AMPK activity is crucial for developing strategies to treat metabolic disorders. Mounting evidence suggests the presence of a link between cyclic AMP (cAMP) and AMPK signaling. cAMP signaling is known to be activated in circumstances of physiological and metabolic stress due to the release of stress hormones, such as adrenaline and glucagon, which is followed by activation of membrane-bound adenylyl cyclase and elevation of cellular cAMP. Because the majority of physiological stresses are associated with elevated energy consumption, it is not surprising that activation of cAMP signaling may promote AMPK activity. Aside from the physiological role of the cAMP/AMPK axis, numerous reports have suggested its role in several pathologies, including inflammation, ischemia, diabetes, obesity, and aging. Furthermore, novel reports have provided more mechanistic insight into the regulation of the cAMP/AMPK axis. In particular, the role of distinct cAMP microdomains generated by soluble adenylyl cyclase in regulating basal and induced AMPK activity has recently been demonstrated. In the present review, we discuss current advances in the understanding of the regulation of the cAMP/AMPK axis and its role in cellular homeostasis and explore some translational aspects.

PGC-1α-Mediated Mitochondrial Quality Control: Molecular Mechanisms and Implications for Heart Failure

Abstract: Mitochondria with structural and functional integrity are essential for maintaining mitochondrial function and cardiac homeostasis. It is involved in the pathogenesis of many diseases. Peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), acted as a transcriptional cofactor, is abundant in the heart, which modulates mitochondrial biogenesis and mitochondrial dynamics and mitophagy to sustain a steady-state of mitochondria. Cumulative evidence suggests that dysregulation of PGC-1α is closely related to the onset and progression of heart failure. PGC-1α deficient-mice can lead to worse cardiac function under pressure overload compared to sham. Here, this review mainly focuses on what is known about its regulation in mitochondrial functions, as well as its crucial role in heart failure.

AMPK and the Adaptation to Exercise.

Abstract: Noncommunicable diseases are chronic diseases that contribute to death worldwide, but these diseases can be prevented and mitigated with regular exercise. Exercise activates signaling molecules and the transcriptional network to promote physiological adaptations, such as fiber type transformation, angiogenesis, and mitochondrial biogenesis. AMP-activated protein kinase (AMPK) is a master regulator that senses the energy state, promotes metabolism for glucose and fatty acid utilization, and mediates beneficial cellular adaptations in many vital tissues and organs. This review focuses on the current, integrative understanding of the role of exercise-induced activation of AMPK in the regulation of system metabolism and promotion of health benefits.

Sestrin2 overexpression attenuates osteoarthritis pain via induction of AMPK/PGC-1α-mediated mitochondrial biogenesis and suppression of neuroinflammation

Abstract: Our previous study indicated that reactive oxygen species (ROS) are critically involved in chronic pain. Sestrin2 (Sesn2), a novel stress-inducible protein, is evidenced to reduce the generation of ROS. The study examined the role of Sesn2 in osteoarthritis (OA) pain and delineated the underlying molecular mechanisms.In the present study, we investigated the impact of Sesn2 on mitochondrial biogenesis in a rat model of OA pain. After adeno-associated viral (AAV)-Sesn2EGFP was injected for 14 days, OA was induced by intra-articular injection of monosodium iodoacetate (MIA). We assessed pain behaviors (weight-bearing asymmetry and paw withdrawal threshold) and explored possible mechanisms in the L4-6 spinal cord.Our results showed that overexpression of Sesn2 in the spinal cord alleviated pain behaviors in OA rats. Moreover, overexpression of Sesn2 increased the activity of AMP-activated protein kinase (AMPK) signaling and significantly restored mitochondrial biogenesis. Besides, Sesn2 overexpression inhibited the activation of astrocytes and microglia, and decreased the production of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the spinal cord of the OA pain rats. These effects were significantly reversed by an AMPK inhibitor.Collectively, these results suggest that Sesn2 overexpression ameliorates mechanical allodynia and weight-bearing asymmetry in OA rats via activation of AMPK/PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Moreover, Sesn2 overexpression attenuates OA-induced neuroinflammation at least partly by activating AMPK signaling. Sesn2 may become an encouraging therapeutic strategy for OA pain relief and other disorders.

Hepatocyte Mitochondrial Dynamics and Bioenergetics in Obesity-Related Non-Alcoholic Fatty Liver Disease

Abstract: Mitochondrial dysfunction has long been proposed to play a crucial role in the pathogenesis of a considerable number of disorders, such as neurodegeneration, cancer, cardiovascular, and metabolic disorders, including obesity-related insulin resistance and non-alcoholic fatty liver disease (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 their formation through biogenesis and the opposite processes of fission and fusion, the fragmentation, and connection of mitochondrial network areas respectively. Herein, we review and discuss the current literature on the significance of mitochondrial adaptations in obesity and metabolic dysregulation, emphasizing on the role of hepatocyte mitochondrial flexibility in obesity and NAFLD.Accumulating evidence suggests the involvement of mitochondrial morphology and bioenergetics dysregulations to the emergence of NAFLD and its progress to non-alcoholic steatohepatitis (NASH). Most relevant data suggests that changes in liver mitochondrial dynamics and bioenergetics hold a key role in the pathogenesis of NAFLD. During obesity and NAFLD, oxidative stress occurs due to the excessive production of ROS, leading to mitochondrial dysfunction. As a result, mitochondria become incompetent and uncoupled from respiratory chain activities, further promoting hepatic fat accumulation, while leading to liver inflammation, insulin resistance, and disease's deterioration. Elucidation of the mechanisms leading to dysfunctional mitochondrial activity of the hepatocytes during NAFLD is of predominant importance for the development of novel therapeutic approaches towards the treatment of this metabolic disorder.

Regulatory networks controlling mitochondrial quality control in skeletal muscle.

Abstract: The adaptive plasticity of mitochondria within skeletal muscle is regulated by signals converging on a myriad of regulatory networks that operate during conditions of increased (i.e. exercise) and decreased (inactivity, disuse) energy requirements. Notably, some of the initial signals that induce adaptive responses are common to both conditions, differing in their magnitude and temporal pattern, to produce vastly opposing mitochondrial phenotypes. In response to exercise, signaling to PGC-1α and other regulators ultimately produces an abundance of high quality mitochondria, leading to reduced mitophagy and a higher mitochondrial content. This is accompanied by the presence of an enhanced protein quality control system that consists of the protein import machinery as well chaperones and proteases termed the UPRmt. The UPRmt monitors intra-organelle proteostasis, and strives to maintain a mito-nuclear balance between nuclear- and mtDNA-derived gene products via retrograde signaling from the organelle to the nucleus. In addition, antioxidant capacity is improved, affording greater protection against oxidative stress. In contrast, chronic disuse conditions produce similar signaling but result in decrements in mitochondrial quality and content. Thus, the interactive cross-talk of the regulatory networks that control organelle turnover during wide variations in muscle use and disuse remain incompletely understood, despite our improving knowledge of the traditional regulators of organelle content and function. This brief review acknowledges existing regulatory networks and summarizes recent discoveries of novel biological pathways involved in determining organelle biogenesis, dynamics, mitophagy, protein quality control and antioxidant capacity, identifying ample protein targets for therapeutic intervention that determine muscle and mitochondrial health.

Chemotherapy impairs skeletal muscle mitochondrial homeostasis in early breast cancer patients

Abstract: Chemotherapy is extensively used to treat breast cancer and is associated with skeletal muscle deconditioning, which is known to reduce patients' quality of life, treatment efficiency, and overall survival. To date, skeletal muscle mitochondrial alterations represent a major aspect explored in breast cancer patients; nevertheless, the cellular mechanisms remain relatively unknown. This study was dedicated to investigating overall skeletal muscle mitochondrial homeostasis in early breast cancer patients undergoing chemotherapy, including mitochondrial quantity, function, and dynamics.

Urolithin A protects dopaminergic neurons in experimental models of Parkinson's disease by promoting mitochondrial biogenesis through the SIRT1/PGC-1α signaling pathway

Abstract: Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). Therapeutic strategies targeting mitochondrial dysfunction hold considerable promise for the treatment of PD. Recent reports have highlighted the protective role of urolithin A (UA), a gut metabolite produced from ellagic acid-containing foods such as pomegranates, berries and walnuts, in several neurological disorders including Alzheimer's disease and ischemic stroke. However, the potential role of UA in PD has not been characterized. In this study, we investigated the underlying mechanisms for role of UA in 6-OHDA-induced neurotoxicity in cell cultures and mice model of PD. Our results revealed that UA protected against 6-OHDA cytotoxicity and apoptosis in PC12 cells. Meanwhile, administration of UA to 6-OHDA lesioned mice ameliorated both motor deficits and nigral-striatal dopaminergic neurotoxicity. More important, UA treatment significantly attenuated 6-OHDA-induced mitochondrial dysfunction in PC12 cells accompanied by enhanced mitochondrial biogenesis. Mechanistically, we demonstrated that UA exerts neuroprotective effects by promoting mitochondrial biogenesis via SIRT1-PGC-1α signaling pathway. Taken together, these data provide new insights into the novel role of UA in regulating mitochondrial dysfunction and suggest that UA may have potential therapeutic applications for PD.

Mitochondrial quality control mechanisms as molecular targets in diabetic heart.

Abstract: Mitochondrial dysfunction has been regarded as a hallmark of diabetic cardiomyopathy. In addition to their canonical metabolic actions, mitochondria influence various other aspects of cardiomyocyte function, including oxidative stress, iron regulation, metabolic reprogramming, intracellular signaling transduction and cell death. These effects depend on the mitochondrial quality control (MQC) system, which includes mitochondrial dynamics, mitophagy and mitochondrial biogenesis. Mitochondria are not static entities, but dynamic units that undergo fission and fusion cycles to maintain their structural integrity. Increased mitochondrial fission elevates the number of mitochondria within cardiomyocytes, a necessary step for cardiomyocyte metabolism. Enhanced mitochondrial fusion promotes communication and cooperation between pairs of mitochondria, thus facilitating mitochondrial genomic repair and maintenance. On the contrary, erroneous fission or reduced fusion promotes the formation of mitochondrial fragments that contain damaged mitochondrial DNA and exhibit impaired oxidative phosphorylation. Under normal/physiological conditions, injured mitochondria can undergo mitophagy, a degradative process that delivers poorly structured mitochondria to lysosomes. However, defective mitophagy promotes the accumulation of nonfunctional mitochondria, which may induce cardiomyocyte death. A decline in the mitochondrial population due to mitophagy can stimulate mitochondrial biogenesis), which generates new mitochondrial offspring to maintain an adequate mitochondrial number. Energy crises or ATP deficiency also increase mitochondrial biogenesis, because mitochondrial DNA encodes 13 subunits of the electron transport chain (ETC) complexes. Disrupted mitochondrial biogenesis diminishes the mitochondrial mass, accelerates mitochondrial senescence and promotes mitochondrial dysfunction. In this review, we describe the involvement of MQC in the pathogenesis of diabetic cardiomyopathy. Besides, the potential targeted therapies that could be applied to improve MQC during diabetic cardiomyopathy are also discussed and accelerate the development of cardioprotective drugs for diabetic patients.

Diet‐induced maternal obesity impacts feto‐placental growth and induces sex‐specific alterations in placental morphology, mitochondrial bioenergetics, dynamics, lipid metabolism and oxidative stress in mice

Abstract: The current study investigated the impact of maternal obesity on placental phenotype in relation to fetal growth and sex.

Oestrogenic Regulation of Mitochondrial Dynamics

Abstract: Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central targets of E2, and their biogenesis and respiration are known to be modulated by E2. More recently, it has become apparent that E2 also regulates mitochondrial fusion–fission dynamics, thereby affecting cellular metabolism. The aim of this article is to discuss the regulatory pathways by which E2 orchestrates the activity of several components of mitochondrial dynamics in the cardiovascular and nervous systems in health and disease. We conclude that E2 regulates mitochondrial dynamics to maintain the mitochondrial network promoting mitochondrial fusion and attenuating mitochondrial fission in both the cardiovascular and nervous systems.

Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis

Abstract: Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.

FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction

Abstract: The mitochondrial integrated stress response (mitoISR) has emerged as a major adaptive pathway to respiratory chain deficiency, but both the tissue specificity of its regulation, and how mitoISR adapts to different levels of mitochondrial dysfunction are largely unknown. Here, we report that diverse levels of mitochondrial cardiomyopathy activate mitoISR, including high production of FGF21, a cytokine with both paracrine and endocrine function, shown to be induced by respiratory chain dysfunction. Although being fully dispensable for the cell-autonomous and systemic responses to severe mitochondrial cardiomyopathy, in the conditions of mild-to-moderate cardiac OXPHOS dysfunction, FGF21 regulates a portion of mitoISR. In the absence of FGF21, a large part of the metabolic adaptation to mitochondrial dysfunction (one-carbon metabolism, transsulfuration, and serine and proline biosynthesis) is strongly blunted, independent of the primary mitoISR activator ATF4. Collectively, our work highlights the complexity of mitochondrial stress responses by revealing the importance of the tissue specificity and dose dependency of mitoISR.

Rhein Ameliorates Cognitive Impairment in an APP/PS1 Transgenic Mouse Model of Alzheimer's Disease by Relieving Oxidative Stress through Activating the SIRT1/PGC-1α Pathway

Abstract: Mitochondrial oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). Recently, antioxidant therapy has been considered an effective strategy for the treatment of AD. Our previous work discovered that rhein relieved mitochondrial oxidative stress in β-amyloid (Aβ) oligomer-induced primary neurons by improving the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha- (PGC-1α-) regulated mitochondrial biogenesis. While encouraging results have been provided, mechanisms underlying the beneficial effect of rhein on AD are yet to be elucidated in vivo. In this study, we evaluated the therapeutic effect of rhein on an APP/PS1 transgenic (APP/PS1) mouse model of AD and explored its antioxidant mechanisms. As a result, rhein significantly reduced Aβ burden and neuroinflammation and eventually ameliorated cognitive impairment in APP/PS1 mice. Moreover, rhein reversed oxidative stress in the brain of APP/PS1 mice and protected neurons from oxidative stress-associated apoptosis. Further study revealed that rhein promoted mitochondrial biogenesis against oxidative stress by upregulating SIRT1 and its downstream PGC-1α as well as nuclear respiratory factor 1. Improved mitochondrial biogenesis not only increased the activity of superoxide dismutase to scavenge excess reactive oxygen species (ROS) but also repaired mitochondria by mitochondrial fusion to inhibit the production of ROS from the electron transport chain. Notably, the exposure of rhein in the brain analyzed by tissue distribution study indicated that rhein could permeate into the brain to exert its therapeutic effects. In conclusion, these findings drive rhein to serve as a promising therapeutic antioxidant for the treatment of AD. Our research highlights the therapeutic efficacy for AD through regulating mitochondrial biogenesis via the SIRT1/PGC-1α pathway.

The Role of SIRT3 in Exercise and Aging

Abstract: The health benefits of regular exercise are well established. Nonetheless, the molecular mechanism(s) responsible for exercise-induced health benefits remain a topic of debate. One of the key cell-signaling candidates proposed to provide exercise-induced benefits is sirtuin 3 (SIRT3). SIRT3, an NAD+ dependent mitochondrial deacetylase, positively modulates many cellular processes, including energy metabolism, mitochondrial biogenesis, and protection against oxidative stress. Although the exercise-induced change in SIRT3 signaling is a potential mechanism contributing to the health advantages of exercise on aging, studies investigating the impact of exercise on SIRT3 abundance in cells provide conflicting results. To resolve this conundrum, this narrative review provides a detailed analysis of the role that exercise-induced changes in SIRT3 play in providing the health and aging benefits associated with regular physical activity. We begin with an overview of SIRT3 function in cells followed by a comprehensive review of the impact of exercise on SIRT3 expression in humans and other mammalians. We then discuss the impact of SIRT3 on aging, followed by a thorough analysis of the cell-signaling links between SIRT3 and exercise-induced adaptation. Notably, to stimulate future research, we conclude with a discussion of key unanswered questions related to exercise, aging, and SIRT3 expression.

Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes

Abstract: Oxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA-encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we tailored ribosome profiling for the unique features of the human mitoribosome.We resolve features of mitochondrial translation initiation and identify a small ORF in the 3' UTR of MT-ND5. Analysis of ribosome footprints in five cell types reveals that average mitochondrial synthesis levels correspond precisely to cytosolic levels across OXPHOS complexes, and these average rates reflect the relative abundances of the complexes. Balanced mitochondrial and cytosolic synthesis does not rely on rapid feedback between the two translation systems, and imbalance caused by mitochondrial translation deficiency is associated with the induction of proteotoxicity pathways.Based on our findings, we propose that human OXPHOS complexes are synthesized proportionally to each other, with mitonuclear balance relying on the regulation of OXPHOS subunit translation across cellular compartments, which may represent a proteostasis vulnerability.

The influence of age, sex, and exercise on autophagy, mitophagy, and lysosome biogenesis in skeletal muscle

Abstract: Aging decreases skeletal muscle mass and quality. Maintenance of healthy muscle is regulated by a balance between protein and organellar synthesis and their degradation. The autophagy-lysosome system is responsible for the selective degradation of protein aggregates and organelles, such as mitochondria (i.e., mitophagy). Little data exist on the independent and combined influence of age, biological sex, and exercise on the autophagy system and lysosome biogenesis. The purpose of this study was to characterize sex differences in autophagy and lysosome biogenesis in young and aged muscle and to determine if acute exercise influences these processes.Young (4-6 months) and aged (22-24 months) male and female mice were assigned to a sedentary or an acute exercise group. Mitochondrial content, the autophagy-lysosome system, and mitophagy were measured via protein analysis. A TFEB-promoter-construct was utilized to examine Tfeb transcription, and nuclear-cytosolic fractions allowed us to examine TFEB localization in sedentary and exercised muscle with age and sex.Our results indicate that female mice, both young and old, had more mitochondrial protein than age-matched males. However, mitochondria in the muscle of females had a reduced respiratory capacity. Mitochondrial content was only reduced with age in the male cohort. Young female mice had a greater abundance of autophagy, mitophagy, and lysosome proteins than young males; however, increases were evident with age irrespective of sex. Young sedentary female mice had indices of greater autophagosomal turnover than male counterparts. Exhaustive exercise was able to stimulate autophagic clearance solely in young male mice. Similarly, nuclear TFEB protein was enhanced to a greater extent in young male, compared to young female mice following exercise, but no changes were observed in aged mice. Finally, TFEB-promoter activity was upregulated following exercise in both young and aged muscle.The present study demonstrates that biological sex influences mitochondrial homeostasis, the autophagy-lysosome system, and mitophagy in skeletal muscle with age. Furthermore, our data suggest that young male mice have a more profound ability to activate these processes with exercise than in the other groups. Ultimately, this may contribute to a greater remodeling of muscle in response to exercise training in males.