Sex-dependent differences in mitochondrial protein acetylation in metabolic condition, oxidative stress, vascular dysfunction, hypertension, and cardiovascular disease

Abstract

One half of adults have hypertension, which is a major risk factor for stroke, myocardial infarction, heart failure, and vascular dementia. There is an urgent need for new therapies, particularly for women with hypertension. Hypertension affects women in all phases of life; however, the hypertension rate increases in women much more steeply, and hypertensive vascular and kidney damage is significantly higher in women. Despite great burden, only 1 in 4 patients have their blood pressure under control. Hypertension accounts for 1 in 5 deaths among American women, posing a greater burden for women than men. Meanwhile, female-specific aspects of hypertension are poorly understood, and women or female-specific risk factors are understudied in basic, clinical, and population research and hypertension guidelines. Understanding these mechanisms can help to develop new therapies. Endothelial dysfunction has a profound prognostic implication predicting adverse cardiovascular events. We suggest that female antihypertensive protection is critically dependent on mitochondrial pathways preserving endothelial function. Metabolic disorders and oxidative stress contribute to the pathogenesis of these conditions, which are linked to mitochondrial dysfunction. Proteomic studies showed higher expression of mitochondrial fatty acid oxidation and antioxidant enzymes in females, and oxidative damage is lower in females compared with males. Meanwhile, the actual activity of these mitochondrial metabolic and antioxidant enzymes is regulated by acetylation, but sex-specific differences in mitochondrial acetylation in vascular disease have not been studied. In the present review, we will discuss potential sex differences in mitochondrial protein acetylation and its implications in metabolic conditions, oxidative stress, vascular dysfunction, hypertension, and cardiovascular disease.

Introduction

Endothelial dysfunction plays a key role in the pathogenesis of hypertension [1], and half of adults in the United States have hypertension, which represents a main risk factor for cardiovascular disease, killing 700,000 people every year in the US alone [2]. Hypertension is a multifactorial disorder (Figure 1) involving perturbations of vasculature, kidney, genetics, central nervous system, endocrine, and immune systems [3]. Recent studies suggest that metabolic conditions are linked to endothelial dysfunction and multi-organ damage, promoting hypertension and cardiovascular disease [4]. It is important to note that all these factors contribute to age-dependent hypertension and cardiovascular disease. Hypertension affects women in all ages, from young adulthood through pregnancy and menopause [5]. It is, however, incorrect to limit the hypertension sex differences to changes in the reproductive cycles, pregnancy, contraceptives, or hormone replacement therapies. The differences in multiple systems including endocrine and metabolic pathways may reduce the prevalence of hypertension in early adulthood among women compared with men [6], but with aging, the hypertension rate increases in women much more steeply, and hypertensive vascular and kidney damage is significantly higher in women [7,8]. Gender-specific aspects of hypertension are still poorly understood. In the present work, we will discuss the potential role of mitochondrial protein acetylation and metabolic and oxidative stress pathways in sex differences in vascular dysfunction, hypertension, and cardiovascular disease.

Figure 1. Multiple causes of hypertension and cardiovascular disease.

Hypertension (HTN) is a multifactorial disorder that is promoted by multiple pathways [9]. Dysregulation of metabolic, immune, endocrine, neural, genetic, and epigenetic pathways and hemodynamics and vascular adaptive responses contribute to the development of hypertension and cardiovascular disease. This figure is modified from our previous publication [10].

More than one-third of mitochondrial proteins are acetylated, which includes key metabolic and antioxidant enzymes [11]. Acetylation of mitochondrial proteins can be both non-enzymatic and enzymatic, and regulatory lysine residues may be particularly sensitive to acetylation [12]. Acetylation and deacetylation of mitochondrial proteins primarily occur on ε-amino group of lysine residues, which depend on multiple factors: diet, lifestyle, Acetyl-CoA level (acetylation substrate), GCN5L1 acetylase, and Sirt3 deacetylase [13,14]. Other enzymes include deacylase Sirt4 (removing methylglutaryl) and Sirt5 (removing succinyl, malonyl, and glutaryl groups from lysine residues) [15]. NAD⁺-dependent Sirt3 is the only identified mitochondrial deacetylase [16]; however, supplementation of NAD⁺ precursors showed very limited effects [17]. Despite the abundance of mitochondrial protein acetylation, the gender-specific differences in mitochondrial acylation and acetylation in cardiovascular disease are not clear. The sections below provide a discussion of the potential role of differential protein acetylation in homeostatic and pathophysiological pathways.

The role of metabolic regulations

Mitochondria are essential cellular ‘powerhouses,’ producing the majority of ATP [18]. Interestingly, mitochondria have several sex-specific features. First, female mitochondria are passed exclusively from mother to child, which is the basis of mitochondrial maternal inheritance [19]. Second, female mitochondria are critical for fertility due to high energy demands of oocyte maturation, fertilization, and early embryo development [20]. Third, female mitochondria require higher ‘quality control’ compared with male mitochondria to minimize mitochondrial damage and reduce mitochondrial dysfunction to support fertility and health of the offsprings [21]. It has been suggested that enhanced quality control, lower production of mitochondrial reactive oxygen species, and increased antioxidant activity contribute to a longer lifespan in women compared with men [22].

Most of the cells utilize both mitochondrial oxidative phosphorylation and glycolysis for ATP production. Recent studies showed that vascular cells have balanced utilization of glycolysis and mitochondrial respiration [23]. It is important to note that mitochondrial dysfunction promotes a maladaptive switch to glycolysis, which is detrimental for vascular and endothelial function [24]. Mitochondrial ATP production is critical for the maintenance of endothelial and epithelial barriers, nutrient transport, and cellular phenotype regulations [23,25–27]. Mitochondrial oxidative phosphorylation utilizes multiple substrates, particularly fatty acids, glucose, and amino acids [28]. Meanwhile, fatty acids are the primary source of energy in multiple cells and tissues, including heart, kidney, and vasculature [29], and impairment of mitochondrial fatty acid β-oxidation is particularly detrimental [27,30]. The sex differences in mitochondrial metabolism are largely ignored. Previously, Busija and colleagues performed proteomic studies of cerebral mouse microvessels, showing that 64 proteins had significantly higher expression in female mitochondria compared with male [31]. Interestingly, mitochondrial responses of cerebral arteries to middle cerebral artery occlusion in females are substantially different from responses seen previously in male rats, suggesting the need for specific sex-based therapies [32].

Analysis of female mitochondria showed higher expression of proteins in energy production, membrane structure, antioxidants, and fatty acid oxidation [31]. These data suggest a substantial difference in substrate utilization between men and women mitochondria. Indeed, recent studies showed that females exhibit higher fat oxidation and more mitochondrial metabolic flexibility, while males display higher rates of glycolysis [33]. Female mitochondria prioritize fatty acid oxidation over carbohydrates during exercise, which is supported by increased mitochondrial volume density and fatty acid and lactate oxidative capacity in skeletal muscle fibers [34]. Meanwhile, male metabolism has a higher reliance on carbohydrates and higher rates of glycolysis [33,35].

We suggest that female antihypertensive protection in early adulthood is critically dependent on metabolic mitochondrial pathways, particularly fatty acid oxidation. Indeed, women aging and menopause are accompanied by decreased fatty acid oxidation and detrimental accumulation of free fatty acids and lipids [36]. Sex hormones can promote fatty acid oxidation and reduce triglycerides and cholesterol, therefore diminishing cardiovascular risk [37]; however, this protection is lost with age. Meanwhile, the precise molecular mechanism remains unknown. Impairment of fatty acid oxidation makes females more susceptible to endothelial dysfunction and hypertension due to higher reliance on fatty acid metabolism [38]. This can be mediated by reduced ATP production, pathogenic intracellular accumulation of fatty acids, and mitochondrial dysfunction [39]. Endothelial fatty acid accumulation promotes oxidative stress, increases vascular inflammation [40], and damages endothelial barrier function [27]. Indeed, impaired fatty acid metabolism promotes endothelial dysfunction and hypertension [41], and high-fat diet induces endothelial dysfunction and accelerates atherosclerosis and hypertension [42], indicating that direct exposure of endothelium to high levels of fatty acids is detrimental [43]. Meanwhile, the actual activity of mitochondrial metabolic enzymes is regulated by acetylation [44], but sex-specific differences in mitochondrial acetylation in vascular disease have not been studied.

Multiple cardiovascular risk factors such as high-fat diet, diabetes, smoking, inflammation, and aging promote acetylation of mitochondrial proteins [13]. This can be mediated by the accumulation of acetyl-CoA, non-enzymatic lysine acetylation, acetyltransferase GCN5L1, or a deficit of deacetylase Sirt3 [24]; however, gender differences between these pathways is not clear. We have previously shown increased acetylation of mitochondrial proteins in patients with essential hypertension associated with Sirt3 deficiency, and Sirt3 knockout mice are prone to hypertension [45]. Our recent study showed that hypertension is linked to an imbalance between acetyltransferase GCN5L1 and deacetylase Sirt3 [24]. Sirt3 induces mitochondrial fatty acid oxidation by deacetylation of long-chain acyl coenzyme A dehydrogenase (LCAD) at K318/322 lysine residues [44,46]. Sirt3 also activates key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2), by deacetylation of specific lysine K68 [47–49]. We propose that females have lower LCAD and SOD2 acetylation; however, an imbalance between Sirt3 deacetylase and GCN5L1-mediated acetylation inactivates LCAD and SOD2 (Figure 2), leading to harmful accumulation of long-chain fatty acids and oxidative stress, promoting endothelial dysfunction and hypertension, particularly in females.

Figure 2. Pathophysiological role of mitochondrial protein acetylation in female cardiovascular health.

We propose that female antihypertensive protection in early adulthood is linked to the reduced acetylation of mitochondrial proteins; however, an imbalance between deacetylase Sirt3 and acetyltransferase GCN5L1 results in the acetylation of critical metabolic and antioxidant enzymes such as LCAD and SOD2, which impair fatty acid oxidation and promote oxidative stress, leading to endothelial dysfunction and the loss of female antihypertensive protection.

It has been suggested that fatty acid oxidation produces acetyl-CoA and therefore promotes protein acetylation [50]. The interplay between fatty acid β-oxidation and protein acetylation is much more complex. First, fatty acid β-oxidation occurs at two sites: mitochondria and peroxisomes [51]. There is a cross-talk between these sites where peroxisomes perform initial oxidation of very-long-chain fatty acids and branched-chain fatty acids into a shorter chain fatty acids for subsequent mitochondrial oxidation [52]. Second, mitochondrial fatty acid β-oxidation is processed by functional fatty acid oxidation-to-electron transport chain multienzyme respirasome complex ensuring that products of one reaction are efficiently passed to the next component without release of acetyl-CoA or other intermediates [50,53]. The resultant acetyl-CoA is passed along to Krebs-cycle for citrate synthesis or immediately transformed to ketone bodies [50]. Third, it was found that peroxisomes rather than mitochondria are the source of mitochondrial protein acetylation [54]. Mitochondria promotes cytoplasmic or nuclei protein acetylation by exporting citrate into cytosol or nucleus where it is transformed into acetyl-CoA [55]. Finaly, metabolic dysfunction, hyperglycemia and high-fat diet lead to pathogenic accumulation of fatty acids, overproduction of acyl-CoA and acetyl-CoA driving deleterious protein hyperacetylation [56].

The role of oxidative stress

Hypertension is strongly associated with oxidative stress due to an imbalance between antioxidant activity and overproduction of reactive oxygen species (ROS; O₂^•- and H₂O₂) by mitochondria, NADPH oxidases, xanthine oxidases, and uncoupled nitric oxide synthase [57–59]. Oxidative stress drives endothelial dysfunction, inflammation, and end-organ damage. Interestingly, there is a redox-dependent regulation of these sources of oxidants, resulting in a feed-forward vicious cycle of oxidative stress [60]. We have previously reported that NADPH oxidases induce mitochondrial ROS production, which in turn increases activity of NADPH oxidases, resulting in mitochondria–NADPH oxidase cross-talk [61], which promotes endothelial dysfunction and development of hypertension [62,63].

Hypertension is associated with both increased production of mitochondrial ROS and inactivation of critical intrinsic antioxidant SOD2 [45,64]. Earlier studies suggested that mitochondrial ROS are ‘by-products’ of oxidative phosphorylation due to ‘spontaneous’ leakage of electrons from the mitochondrial electron transport chain [65]. We think this is an artefact of in vitro experiments with isolated mitochondria in air-saturated hyperoxia media (20% oxygen versus 5% in vivo) and maximal substrate concentration above Km showing significant superoxide production in the mitochondrial matrix and substantial release of H₂O₂ outside of mitochondria [66]. Cell damage, inflammation, and metabolic alterations can induce mitochondrial ROS production by modulation of specific enzymatic functions, and this is not a ‘spontaneous’ leakage of electrons to oxygen as previously suggested. Specific activation of PKCε induces mitochondrial superoxide production via reverse electron transfer to the ubiquinone site of complex I, while blocking the PKCε with a specific peptide inhibitor or targeting reverse electron transfer (malonate or rotenone) prevents overproduction of mitochondrial superoxide and reduces vascular oxidative stress and hypertension [62,63]. SOD2 level was not changed in patients with essential hypertension; however, the SOD2 activity was markedly reduced due to specific acetylation of the highly conserved catalytic center SOD2 lysine 68 [45,67]. SOD2 acetylation is controlled by acetyltransferase GCN5L1 and deacetylase Sirt3, and imbalance between GCN5L1 and Sirt3 (Figure 3) promotes SOD2 acetylation in hypertension [24].

Figure 3. Metabolic dysfunction-oxidative stress crosstalk.

The crosstalk between metabolic dysfunction and mitochondrial oxidative stress induces Sirt3/GCN5L1 imbalance driving protein acetylation and mitochondrial dysfunction. PUFA, polyunsaturated fatty acids; IsoLGs, reactive dialdehyde isolevuglandins; ETC, electron transport chain.

Despite similar expression of SOD2 in males and females [31], the SOD2 activity is higher in females compared with males [68]. This can be due to diminished SOD2 acetylation in female mitochondria. Indeed, the deacetylation mimetic SOD2-K68R mutation reduced angiotensin II-induced hypertension by 24 mmHg in males, while in SOD2-K68R female mice, hypertension was decreased only by 10 mmHg. The potential benefits of increased SOD2 activity can be smaller in females compared with males due to higher basal SOD2 activity in females. We suggest that this antioxidant protection is lacking in female patients with cardiovascular risk factors such as metabolic conditions, salt sensitivity, smoking, menopause, and aging [13,69].

We have developed mitochondria-targeted SOD2 mimetics, which can compensate for SOD2 inactivation including mitoTEMPO, mCP1, and mCP2 [70,71]. Mitochondria-targeted SOD2 mimetics protect mitochondrial respiration, reduce vascular oxidative stress, improve endothelial nitric oxide production, and reduce hypertension [71]. Interestingly, SOD2 acetylation is a redox-dependent process, and it can be reversed and normalized. For example, scavenging of mitochondrial H₂O₂ by mitoEbselen and mitochondria-targeted catalase improved Sirt3 activity, rescued SOD2 deacetylation, and reduced vascular oxidative stress and hypertension [45]. These data support the pathophysiological role of SOD2 acetylation in vascular disease and hypertension. Meanwhile, sex-specific role of SOD2 acetylation in female-specific risk factors is understudied in basic, clinical, and population research.

Acetylation of mitochondrial electron transport chain and Krebs cycle enzymes may include complex I–V, isocitrate dehydrogenase, aconitase, and pyruvate dehydrogenase [72]. This not only impairs oxidative phosphorylation but also reduces antioxidant activity due to diminished NADPH production and increases mitochondrial ROS production due to the accumulation of metabolic substrates and overreduction of electron transport chain [56]. The interplay between acetylation of metabolic enzymes and oxidative stress is not well studied.

Mitochondrial oxidative stress leads to lipid peroxidation of polyunsaturated fatty acids such as arachidonic acid and results in the formation of highly toxic lipid peroxidation products, isolevuglandins [73], that cause an imbalance between mitochondrial protein acetylation and deacetylation (Figure 3) [24]. Human hypertension is linked to increased production of isolevuglandins [74], and animal studies showed that blocking mitochondrial isolevuglandins with mitochondria-targeted mito2HOBA improves mitochondrial function, rescues endothelial nitric oxide production and vasorelaxation, and reduces hypertension. It is important to note that isolevuglandins are highly reactive dicarbonyls rapidly making protein adducts that activate dendritic cells, induce T cells promoting cytokine production, vascular alterations, kidney damage, and hypertension [74–76]. Isolevuglandins can represent an important new therapeutic target, particularly considering interaction of oxidative stress and fatty acid accumulation associated with mitochondrial dysfunction described above.

Inflammation and mitochondria

Although multiple interdependent pathways contribute to hypertension and cardiovascular disease [77], it has become clear that inflammation represents a key node in these pathological conditions [78,79]. Chronic inflammation is both the cause and the consequence of hypertension mediated by activation of T cells, monocytes, macrophages, dendritic cells, B cells, and natural killer cells. Inflammatory pathways are prompted by hormones, salt, mechanical stretch, and metabolic conditions inducing NLRP3 inflammasome, isolevuglandin-adducted peptides, and their processing by the immunoproteasome [78,79]. The critical contribution of inflammation in hypertension and cardiovascular disease has been extensively studied. In the present work, we would like to highlight the potential role of mitochondria and protein acetylation in these conditions. First, mitochondrial damage directly induces NLRP3 inflammasome due to the release of damage-associated molecular patterns (DAMPs) from mitochondria such as mtDNA [80]. Second, mitochondrial ROS induces NLRP3-dependent inflammasome activation [81]. Third, Sirt3 deficiency and acetylation of mitochondrial proteins increase NLRP3 inflammasome and NF-κB activity [67]. Finally, lipid peroxidation product isolevuglandins-peptide adducts are processed by immunoproteasome in dendritic and endothelial cells [76] and presented by murine class I major histocompatibility complex in hypertensive tissue [82] to promote inflammation, vascular dysfunction, and hypertension. Interestingly, these proinflammatory mechanisms are dependent on acetylation of mitochondrial proteins. Depletion of mitochondrial GCN5L1 acetyltransferase markedly reduced production of inflammatory cytokines [83], while mitochondrial deacetylase Sirt3 reduces inflammation and attenuates endotoxin-induced lung injury [84]. This can be mediated by deacetylation/activation of critical mitochondrial antioxidant SOD2 and protection from mitochondrial permeability transition pore opening, inducing cell death. Indeed, we showed that SOD2-K68R [85] and CypD-K166R [24] deacetylation mimetic mice were cytokine-resistant and protected from cytokine-induced endothelial dysfunction and hypertension. Furthermore, genetic overexpression of mitochondrial deacetylase Sirt3 reduces NLRP3 and NF-κB activation, diminished markers of endothelial inflammation VCAM and ICAM, and abolished inflammatory cell infiltration in vascular tissue [67]. Of note, mitochondrial acetylation affects NF-κB and NLRP3 pathways indirectly by increasing production of mitochondrial ROS [86] and mitochondrial damage releasing DAMPs, which activates NLRP3 inflammasomes [87]. These data strongly support the novel role of mitochondria and protein acetylation in inflammatory mechanisms of vascular disease, hypertension, and cardiovascular conditions. It is conceivable that sex differences in mitochondrial quality and protein acetylation such as SOD2 and CypD contribute to the increased rates of hypertensive vascular and kidney damage in women.

Endocrine dysregulations

It has been shown that estrogen is an important regulator of mitochondrial function, ATP production, mitochondrial biogenesis, and fatty acid metabolism [88,89]. The hormonal changes make postmenopausal women particularly vulnerable to muscle loss and abdominal obesity, which can be affected by a sedentary lifestyle due to changes in energy expenditure and metabolic rate [89]. Animal studies showed that protective effects of estrogen [90] are Sirt3 dependent and are lacking in Sirt3^−/− mice [91], which suggests a potential link between estrogen and mitochondrial acetylation.

Angiotensin II is a critical hormone in the renin–angiotensin–aldosterone system regulating blood pressure and sodium and water retention; however, dysregulation of angiotensin II pathways contributes to hypertension and cardiovascular and kidney disease [92]. In females, the expression of the protective angiotensin type 2 receptor is driven by estrogen, and the type 2/type 1 receptor balance is lost with age and menopause [93,94]. Angiotensin II type 1 receptor has higher expression in males [95], and it can drive activation of redox-dependent NADPH oxidases [63]. Protective angiotensin type 2 receptor is increased in females and promotes mitochondrial biogenesis and increases sirtuins’ activity [96]. These data support the cross-talk between the endocrine system and mitochondria. Additional studies can provide further mechanistic insight and novel pharmacological targets.

Genetic and epigenetic mechanisms

Genome-wide association studies showed more than 100 variants associated with blood pressure; however, these factors have typically small effect sizes and could explain about 3.5% of blood pressure variability [97]. Sixty-two genes are proposed to have an association with primary hypertension, but only 21 genes have nearly 50% of positive associations [98]. It has been suggested that genetic variants contribute more to high blood pressure in women than in men, leading to higher genetic risk for the development of hypertension in early adulthood [99]. Estrogen receptor-β gene variation is associated with salt-sensitive hypertension in premenopausal women [98], which can potentially include metabolic and mitochondrial effects. The interaction of estrogen decline and genetic factors contributes to accelerated vascular aging [100]. Despite tremendous progress in genetic studies, there are gaps in knowledge about the role of age, sex hormones, genetics, and lifestyles in the development of hypertension and cardiovascular disease.

Recent studies implicate epigenetic modifications in the pathophysiology of essential hypertension [101]. Epigenetics refers to reversible DNA methylation and histone modifications that alter gene expression without changing the DNA sequence. Epigenetic factors are affected by maternal diet, stress, smoking, environmental pollutants, and physical activity [102]. It is important that epigenetic modulation is transmitted to offspring and affect susceptibility to metabolic and cardiovascular diseases for multiple generations [103]. Mitochondrion is key player in epigenetic modulation due to the essential role of mitochondrial metabolic intermediates (acetyl-CoA, NAD⁺, and α-ketoglutarate) for epigenetic enzymes [104]; therefore, mitochondrial metabolism directly affects the epigenetic remodeling, connecting modifiable lifestyle factors with gene expression. This is retrograde signaling where mitochondria send signals to the nucleus to induce changes in gene transcription, which affects cell adaptation and function. As we discussed above, female mitochondrial metabolism is uniquely turned for fatty acid oxidation, which is a major source of acetyl-CoA and other metabolites affecting epigenetics. Dysfunctional mitochondria drive pathogenic epigenetic changes promoting ovarian aging and reducing longevity [105]. Interestingly, targeting mitochondrial function, such as time-restricted eating, exercise, and diet, can improve the epigenetic landscape [106].

Vascular dysregulations

Vascular disease affects both genders; however, women are more likely to have worse outcomes due to delayed diagnosis and atypical symptoms [107]. Hypertensive vascular damage is much higher in women [7,8], and sex-specific aspects of hypertension are poorly understood [108]. Mitochondrial dysfunction promotes vascular disease due to increased inflammation, oxidative stress, and endothelial dysfunction [109]. Mitochondrial ATP is critical for nitric oxide production and endothelial-dependent relaxation [25], and impaired mitochondrial fatty acid oxidation drives pathogenic endothelial-to-mesenchymal transition [27]. It has been previously suggested that endothelial cells rely on glycolysis [110] instead of mitochondrial respiration, suggesting a minor role of mitochondria in endothelial metabolism. Recent studies demonstrated a balanced utilization of glycolysis and mitochondrial respiration by vascular cells [23], which are normally coupled [111], meaning that glycolysis product pyruvate is utilized by mitochondria. We have shown that mitochondrial dysfunction in hypertension leads to uncoupled glycolysis, i.e., glycolysis is disproportionately increased compared with mitochondrial respiration [24,112]. The increase in vascular glycolysis in hypertension is linked to glycolytic metabolism in endothelium, smooth muscle cells, fibroblasts, and inflammatory cells. Our data show 10-fold increase in endothelial glycolysis in hypertension due to hyperacetylation of mitochondrial proteins, and blocking mitochondrial dysfunction reduces endothelial glycolysis by 50% [24]. The pathophysiological role of glycolytic switches in vascular smooth muscle cells and adventitial fibroblasts [113] promotes aortic aneurysms and vascular fibrosis [114], and inhibition of vascular glycolysis reduces aneurysmal formation and diminishes mortality due to reduced aortic ruptures [115,116]. These data support the novel role of mitochondrial protein acetylation in vascular disease; however, its specific mechanism and sex-specific role remained understudied.

Central nervous system

Psychological stress, high salt intake, angiotensin II, obesity, and insulin resistance stimulate specific brain areas such as the subfornical organ [117], hypothalamus, and rostral ventrolateral medulla [118], inducing oxidative stress and inflammation [119,120], which increases sympathetic outflow to promote vasoconstriction and salt retention, driving vascular and kidney damage. Interestingly, metabolic abnormalities particularly promote the sympathetic nervous system activity, which can further exacerbate metabolic dysfunction [121,122]. The interplay between the central nervous system and metabolic disorders can drive the sympathetic nervous system activity, inflammation, and oxidative stress, promoting hypertension and hypertensive organ damage. Interestingly, there are sex and race differences in these pathways. For example, sympathetic activity was elevated in obese white women with hypertension, and trimethaphan reduced blood pressure in hypertensive patients compared with those with normotension (−26.8 mm Hg versus −14.8 mm Hg) [123]. Meanwhile, there was no difference in the depressor responses induced by trimethaphan between obese black women with and without hypertension. It is suggested that premenopausal women are protected from obesity-induced metabolic complications; however, postmenopausal estrogen deprivation can promote sympathetic activity [124]. Metabolic disorders can affect multiple central nervous system pathways [121], particularly mitochondrial function [125]. Metabolic disorders play a critical role in hypertension and cardiovascular disease [126], this may include the central and peripheral role of mitochondria. Recent studies of brain mitochondrial proteome acetylation showed higher reliance on Sirt3-mediated deacetylation in females compared with males, and Sirt3 deficiency promoted behavioral changes [127]. It has been suggested that Sirt3 activation can be used for the treatment of neurodegenerative conditions [128]. We think that mitochondrial resilience is important for neurovascular and nervous systems, and new studies can provide novel mechanistic insight into the role of protein acetylation and support for new pharmacological targeting of mitochondria.

Conclusion

In the present work, we have discussed different metabolic, oxidative stress, inflammatory, endocrine, genetic, vascular, and central pathways, with the emphasis on the role of mitochondria in these pathways contributing to the development of hypertension and cardiovascular disease. In the past two decades, we have made significant progress in understanding the molecular mechanisms of these pathological conditions, which now include a critical role of mitochondrial function. Meanwhile, the growing ‘epidemic’ of metabolic disease [129] combined with ∼50% prevalence of hypertension in the adult population [130] highlights the unmet need for new strategies to prevent, diagnose, and treat these conditions. Both hypertension and metabolic disease are linked to impaired fatty acid oxidation and oxidative stress associated with mitochondrial dysfunction; however, there are no clinically approved mitochondria-targeted treatments. We have a substantial gap of knowledge, and there is still a lot to be done. First, we must recognize an unmet need for treatment of pulmonary, cardiovascular, and kidney diseases, particularly in women. Women’s or female-specific risk factors are understudied in basic, clinical, and population research and hypertension guidelines. Sex-specific risk factors remained understudied in basic, clinical, and population research. Second, many basic science discoveries are lost in translation. We know that oxidative stress and mitochondrial dysfunction play an important role in cardiovascular disease; however, supplementation with common antioxidants like vitamin C and vitamin E is not effective, and mitochondria-targeted therapies are not available. We think that previously used antioxidants did not target the critical sources of oxidants such as mitochondria, and we are only beginning to understand how we should manipulate and normalize the acetylation of mitochondrial proteins, which is critical for mitochondrial health. Finally, we need to embrace the new paradigm for the critical role of fatty acid oxidation in human health rather than support ‘fat-free’ diets, and we need to invest in mitochondrial studies showing therapeutic promise for nutritional supplements and mitochondrial transplantation. Future translational studies must define the most important mitochondrial targets and effective therapeutic approaches to offset the pathological mechanisms responsible for impaired fatty acid oxidation, mitochondrial dysfunction, and oxidative stress.

Abbreviations

DAMPs

damage-associated molecular patterns

LCAD

long-chain acyl coenzyme A dehydrogenase

ROS

reactive oxygen species

SOD2

superoxide dismutase 2

Sirt3

sirtuin 3, mitochondrial deacetylase

GCN5L1

general control of amino acid synthesis 5 like 1

IsoLGs

isolevuglandins, highly reactive dialdehydes

ETC

electron transport chain

PUFA

polyunsaturated fatty acids

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

The present work was supported by funding from the National Institutes of Health [R01HL144943, RO1HL157583 and 1R01HL183432]. Dr. Dikalova was supported by American Heart Association Transformational Project Awards [23TPA1077648 and 24TPA1300869].

Open Access

Open access for this article was enabled by the participation of Vanderbilt University in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society.

CRediT Author Contribution

A.D. and S.D. Conceptualized the manuscript. S.D. Wrote the manuscript and Prepared figures. A.D. Edited & revised the manuscript. A.D and S.D. Approved the final version of the manuscript.