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Cardiolipin deficiency elevates susceptibility to a lipotoxic hypertrophic cardiomyopathy

Laura K Cole, Edgard M Mejia, Genevieve C Sparagna, Marilyne Vandel, Bo Xiang, Xianlin Han, Nikolaos Dedousis, Brett A Kaufman, Vernon W Dolinsky, Grant M Hatch
J Mol Cell Cardiol. 2020 Jul:144:24-34. doi: 10.1016/j.yjmcc.2020.05.001. Epub 2020 May 11.

Abstract:

Cardiolipin (CL) is a unique tetra-acyl phospholipid localized to the inner mitochondrial membrane and essential for normal respiratory function. It has been previously reported that the failing human heart and several rodent models of cardiac pathology have a selective loss of CL. A rare genetic disease, Barth syndrome (BTHS), is similarly characterized by a cardiomyopathy due to reduced levels of cardiolipin. A mouse model of cardiolipin deficiency was recently developed by knocking-down the cardiolipin biosynthetic enzyme tafazzin (TAZ KD). These mice develop an age-dependent cardiomyopathy due to mitochondrial dysfunction. Since reduced mitochondrial capacity in the heart may promote the accumulation of lipids, we examined whether cardiolipin deficiency in the TAZ KD mice promotes the development of a lipotoxic cardiomyopathy. In addition, we investigated whether treatment with resveratrol, a small cardioprotective nutraceutical, attenuated the aberrant lipid accumulation and associated cardiomyopathy. Mice deficient in tafazzin and the wildtype littermate controls were fed a low-fat diet, or a high-fat diet with or without resveratrol for 16 weeks. In the absence of obesity, TAZ KD mice developed a hypertrophic cardiomyopathy characterized by reduced left-ventricle (LV) volume (~36%) and 30-50% increases in isovolumetric contraction (IVCT) and relaxation times (IVRT). The progression of cardiac hypertrophy with tafazzin-deficiency was associated with several underlying pathological processes including altered mitochondrial complex I mediated respiration, elevated oxidative damage (~50% increase in reactive oxygen species, ROS), the accumulation of triglyceride (~250%) as well as lipids associated with lipotoxicity (diacylglyceride ~70%, free-cholesterol ~44%, ceramide N:16-35%) compared to the low-fat fed controls. Treatment of TAZ KD mice with resveratrol maintained normal LV volumes and preserved systolic function of the heart. The beneficial effect of resveratrol on cardiac function was accompanied by a significant improvement in mitochondrial respiration, ROS production and oxidative damage to the myocardium. Resveratrol treatment also attenuated the development of cardiac steatosis in tafazzin-deficient mice through reduced de novo fatty acid synthesis. These results indicate for the first time that cardiolipin deficiency promotes the development of a hypertrophic lipotoxic cardiomyopathy. Furthermore, we determined that dietary resveratrol attenuates the cardiomyopathy by reducing ROS, cardiac steatosis and maintaining mitochondrial function.

Keywords: Hypertrophy; Lipotoxicity; Mitochondria; Oxidative stress; Resveratrol.


Rapamycin rejuvenates oral health in aging mice

Jonathan Y An, Kristopher A Kerns, Andrew Ouellette, Laura Robinson, H Douglas Morris, Catherine Kaczorowski, So-Il Park, Title Mekvanich, Alex Kang, Jeffrey S McLean, Timothy C Cox, Matt Kaeberlein
Elife. 2020 Apr 28:9:e54318. doi: 10.7554/eLife.54318.

Abstract:

Periodontal disease is an age-associated disorder clinically defined by periodontal bone loss, inflammation of the specialized tissues that surround and support the tooth, and microbiome dysbiosis. Currently, there is no therapy for reversing periodontal disease, and treatment is generally restricted to preventive measures or tooth extraction. The FDA-approved drug rapamycin slows aging and extends lifespan in multiple organisms, including mice. Here, we demonstrate that short-term treatment with rapamycin rejuvenates the aged oral cavity of elderly mice, including regeneration of periodontal bone, attenuation of gingival and periodontal bone inflammation, and revertive shift of the oral microbiome toward a more youthful composition. This provides a geroscience strategy to potentially rejuvenate oral health and reverse periodontal disease in the elderly.

Keywords: aging; cell biology; dentistry; gum disease; immunology; inflammaging; inflammation; microbiome; mouse; rapamycin.


Hepatic Choline Transport Is Inhibited During Fatty Acid-Induced Lipotoxicity and Obesity

Conor O’Dwyer, Rebecca Yaworski, Sakie Katsumura, Peyman Ghorbani, Kaelan Gobeil Odai, Julia R C Nunes, Nicholas D LeBlond, Sabrin Sanjana, Tyler T K Smith, Shauna Han, Kaitlyn D Margison, Tommy Alain, Masahiro Morita, Morgan D Fullerton
Hepatol Commun. 2020 Apr 10;4(6):876-889. doi: 10.1002/hep4.1516. eCollection 2020 Jun.

Abstract:

Choline is an essential nutrient and a critical component of the membrane phospholipid phosphatidylcholine (PC), the neurotransmitter acetylcholine, while also contributing to the methylation pathway. In the liver specifically, PC is the major membrane constituent and can be synthesized by the cytidine diphosphate-choline or the phosphatidylethanolamine N-methyltransferase pathway. With the continuing global rise in the rates of obesity and nonalcoholic fatty liver disease, we sought to explore how excess fatty acids on primary hepatocytes and diet-induced obesity affect choline uptake and metabolism. Our results demonstrate that hepatocytes chronically treated with palmitate, but not oleate or a mixture, had decreased choline uptake, which was associated with lower choline incorporation into PC and lower expression of choline transport proteins. Interestingly, a reduction in the rate of degradation spared PC levels in response to palmitate when compared with control. The effects of palmitate treatment were independent of endoplasmic reticulum stress, which counterintuitively augmented choline transport and transporter expression. In a model of obesity-induced hepatic steatosis, male mice fed a 60% high-fat diet for 10 weeks had significantly diminished hepatic choline uptake compared with lean mice fed a control diet. Although the transcript and protein expression of various choline metabolic enzymes fluctuated slightly, we observed reduced protein expression of choline transporter-like 1 (CTL1) in the liver of mice fed a high-fat diet. Polysome profile analyses revealed that in livers of obese mice, the CTL1 transcript, despite being more abundant, was translated to a lesser extent compared with lean controls. Finally, human liver cells demonstrated a similar response to palmitate treatment. Conclusion: Our results suggest that the altered fatty acid milieu seen in obesity-induced fatty liver disease progression may adversely affect choline metabolism, potentially through CTL1, but that compensatory mechanisms work to maintain phospholipid homeostasis.


The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action

Wayne Mitchell, Emily A Ng, Jeffrey D Tamucci, Kevin J Boyd, Murugappan Sathappa, Adrian Coscia, Meixia Pan, Xianlin Han, Nicholas A Eddy, Eric R May, Hazel H Szeto, Nathan N Alder
J Biol Chem. 2020 May 22;295(21):7452-7469. doi: 10.1074/jbc.RA119.012094. Epub 2020 Apr 9.

Abstract:

Mitochondrial dysfunction underlies many heritable diseases, acquired pathologies, and aging-related declines in health. Szeto-Schiller (SS) peptides comprise a class of amphipathic tetrapeptides that are efficacious toward a wide array of mitochondrial disorders and are believed to target mitochondrial membranes because they are enriched in the anionic phospholipid cardiolipin (CL). However, little is known regarding how SS peptides interact with or alter the physical properties of lipid bilayers. In this study, using biophysical and computational approaches, we have analyzed the interactions of the lead compound SS-31 (elamipretide) with model and mitochondrial membranes. Our results show that this polybasic peptide partitions into the membrane interfacial region with an affinity and a lipid binding density that are directly related to surface charge. We found that SS-31 binding does not destabilize lamellar bilayers even at the highest binding concentrations; however, it did cause saturable alterations in lipid packing. Most notably, SS-31 modulated the surface electrostatics of both model and mitochondrial membranes. We propose nonexclusive mechanisms by which the tuning of surface charge could underpin the mitoprotective properties of SS-31, including alteration of the distribution of ions and basic proteins at the interface, and/or modulation of bilayer physical properties. As a proof of concept, we show that SS-31 alters divalent cation (calcium) distribution within the interfacial region and reduces the energetic burden of calcium stress in mitochondria. The mechanistic details of SS-31 revealed in this study will help inform the development of future compound variants with enhanced efficacy and bioavailability.

Keywords: SS-31; Szeto-Schiller peptide; bioenergetics; cardiolipin; drug action; elamipretide; electrostatics; inner membrane; lipid structure; membrane biophysics; mitochondria; peptide therapeutic; peptides.

 


Awakening the dark side: retrotransposon activation in neurodegenerative disorders

Elizabeth Ochoa Thomas, Gabbe Zuniga, Wenyan Sun, Bess Frost.
Current Opinion in Neurobiology. 2020 Apr;61:65-72. doi: 10.1016/j.conb.2020.01.012. Epub 2020 Feb 21.

Abstract:

Nearly half (45%) of the human genome is composed of transposable elements, or ‘jumping genes’. Since Barbara McClintock’s original discovery of transposable elements in 1950, we have come to appreciate that transposable element mobilization is a major driver of evolution that transposons are active in the germline and the soma, and that transposable element dysregulation is causally associated with many human disorders. In the present review, we highlight recent studies investigating transposable element activation in the adult brain and in the context of neurodegeneration. Collectively, these studies contribute to a greater understanding of the frequency of complete retrotransposition in the adult brain as well as the presence of transposable element-derived RNA and protein in brain and fluids of patients with neurodegenerative disorders. We discuss therapeutic opportunities and speculate on the larger implications of transposable element activation in regard to current hot topics in the field of neurodegeneration.


Thioredoxin overexpression in mitochondria showed minimum effects on aging and age-related diseases in male C57BL/6 mice

Madeline G Roman, Lisa C Flores, Geneva M Cunningham, Christie Cheng, Sara Dube, Colton Allen, Holly Van Remmen, Yidong Bai, Gene B Hubbard, Thomas L Saunders, Yuji Ikeno
Aging Pathobiol Ther. 2020;2(1):20-31. doi: 10.31491/apt.2020.03.009. Epub 2020 Mar 27.

Abstract:

Objective: In this study, the effects of overexpression of thioredoxin 2 (Trx2) on aging and age-related diseases were examined using Trx2 transgenic mice [Tg(TXN2]+/0]. Because our previous studies demonstrated that thioredoxin (Trx) overexpression in the cytosol (Trx1) did not extend maximum lifespan, this study was conducted to test if increased Trx2 expression in mitochondria shows beneficial effects on aging and age-related pathology.

Methods: Trx2 transgenic mice were generated using a fragment of the human genome containing the TXN2 gene. Effects of Trx2 overexpression on survival, age-related pathology, oxidative stress, and redox-sensitive signaling pathways were examined in male Tg(TXN2)+/0 mice.

Results: Trx2 levels were significantly higher (approximately 1.6- to 5-fold) in all of the tissues we examined in Tg(TXN2)+/0 mice compared to wild-type (WT) littermates, and the expression levels were maintained during aging (up to 22-24 months old). Trx2 overexpression did not alter the levels of Trx1, glutaredoxin, glutathione, or other major antioxidant enzymes. Overexpression of Trx2 was associated with reduced reactive oxygen species (ROS) production from mitochondria and lower isoprostane levels compared to WT mice. When we conducted the survival study, male Tg(TXN2)+/0mice showed a slight extension (approximately 8-9%] of mean, median, and 10th percentile lifespans; however, the survival curve was not significantly different from WT mice. Cross-sectional pathological analysis (22-24 months old) showed that Tg(TXN2)+/0 mice had a slightly higher severity of lymphoma; however, tumor burden, disease burden, and severity of glomerulonephritis and inflammation were similar to WT mice. Trx2 overexpression was also associated with higher c-Jun and c-Fos levels; however, mTOR activity and levels of NFκB p65 and p50 were similar to WT littermates.

Conclusions: Our findings suggest that the increased levels of Trx2 in mitochondria over the lifespan in Tg(TXN2)+/0 mice showed a slight life-extending effect, reduced ROS production from mitochondria and oxidative damage to lipids, but showed no significant effects on aging and age-related diseases.

Keywords: Thioredoxin; aging; oxidative stress; transgenic Mouse.


Mitochondrial-targeted methionine sulfoxide reductase overexpression increases the production of oxidative stress in mitochondria from skeletal muscle

Arunabh Bhattacharya, Daniel Pulliam, Yuhong Liu, Adam B Salmon
Aging Pathobiol Ther. 2020;2(1):45-51. doi: 10.31491/apt.2020.03.012. Epub 2020 Mar 27.

Abstract:

Objective: Mitochondrial dysfunction comprises part of the etiology of myriad health issues, particularly those that occur with advancing age. Methionine sulfoxide reductase A (MsrA) is a ubiquitous protein oxidation repair enzyme that specifically and catalytically reduces a specific epimer of oxidized methionine: methionine sulfoxide. In this study, we tested the ways in which mitochondrial bioenergetic functions are affected by increasing MsrA expression in different cellular compartments.

Methods: In this study, we tested the function of isolated mitochondria, including free radical generation, ATP production, and respiration, from the skeletal muscle of two lines of transgenic mice with increased MsrA expression: mitochondria-targeted MsrA overexpression or cytosol-targeted MsrA overexpression.

Results: Surprisingly, in the samples from mice with mitochondrial-targeted MsrA overexpression, we found dramatically increased free radical production though no specific defect in respiration, ATP production, or membrane potential. Among the electron transport chain complexes, we found the activity of complex I was specifically reduced in mitochondrial MsrA transgenic mice. In mice with cytosolic-targeted MsrA overexpression, we found no significant alteration made to any of these parameters of mitochondrial energetics.

Conclusions: There is also a growing amount of evidence that MsrA is a functional requirement for sustaining optimal mitochondrial respiration and free radical generation. MsrA is also known to play a partial role in maintaining normal protein homeostasis by specifically repairing oxidized proteins. Our studies highlight a potential novel role for MsrA in regulating the activity of mitochondrial function through its interaction with the mitochondrial proteome.

Keywords: Superoxide; electron transport chain; mitochondria; oxidative stress; protein homeostasis.


4E-BP-Dependent Translational Control of Irf8 Mediates Adipose Tissue Macrophage Inflammatory Response

Dana Pearl, Sakie Katsumura, Mehdi Amiri, Negar Tabatabaei, Xu Zhang, Valerie Vinette, Xinhe Pang, Shawn T Beug, Sung-Hoon Kim, Laura M Jones, Nathaniel Robichaud, Sang-Ging Ong, Jian-Jun Jia, Hamza Ali, Michel L Tremblay, Maritza Jaramillo, Tommy Alain, Masahiro Morita, Nahum Sonenberg, Soroush Tahmasebi
J Immunol. 2020 May 1;204(9):2392-2400. doi: 10.4049/jimmunol.1900538. Epub 2020 Mar 25.

Abstract:

Deregulation of mRNA translation engenders many human disorders, including obesity, neurodegenerative diseases, and cancer, and is associated with pathogen infections. The role of eIF4E-dependent translational control in macrophage inflammatory responses in vivo is largely unexplored. In this study, we investigated the involvement of the translation inhibitors eIF4E-binding proteins (4E-BPs) in the regulation of macrophage inflammatory responses in vitro and in vivo. We show that the lack of 4E-BPs exacerbates inflammatory polarization of bone marrow-derived macrophages and that 4E-BP-null adipose tissue macrophages display enhanced inflammatory gene expression following exposure to a high-fat diet (HFD). The exaggerated inflammatory response in HFD-fed 4E-BP-null mice coincides with significantly higher weight gain, higher Irf8 mRNA translation, and increased expression of IRF8 in adipose tissue compared with wild-type mice. Thus, 4E-BP-dependent translational control limits, in part, the proinflammatory response during HFD. These data underscore the activity of the 4E-BP-IRF8 axis as a paramount regulatory mechanism of proinflammatory responses in adipose tissue macrophages.


Mobilization-based transplantation of young-donor hematopoietic stem cells extends lifespan in mice

Michael J Guderyon, Cang Chen, Anindita Bhattacharjee, Guo Ge, Roman A Fernandez, Jonathan A L Gelfond, Karla M Gorena, Catherine J Cheng, Yang Li, James F Nelson, Randy J Strong, Peter J Hornsby, Robert A Clark, Senlin Li
Aging Cell. 2020 Mar;19(3):e13110. doi: 10.1111/acel.13110. Epub 2020 Feb 3.

Abstract:

Mammalian aging is associated with reduced tissue regeneration and loss of physiological integrity. With age, stem cells diminish in their ability to regenerate adult tissues, likely contributing to age-related morbidity. Thus, we replaced aged hematopoietic stem cells (HSCs) with young-donor HSCs using a novel mobilization-enabled hematopoietic stem cell transplantation (HSCT) technology as an alternative to the highly toxic conditioning regimens used in conventional HSCT. Using this approach, we are the first to report an increase in median lifespan (12%) and a decrease in overall mortality hazard (HR: 0.42, CI: 0.273-0.638) in aged mice following transplantation of young-donor HSCs. The increase in longevity was accompanied by reductions of frailty measures and increases in food intake and body weight of aged recipients. Young-donor HSCs not only preserved youthful function within the aged bone marrow stroma, but also at least partially ameliorated dysfunctional hematopoietic phenotypes of aged recipients. This compelling evidence that mammalian health and lifespan can be extended through stem cell therapy adds a new category to the very limited list of successful anti-aging/life-extending interventions. Our findings have implications for further development of stem cell therapies for increasing health and lifespan.

Keywords: Aging; age-associated health deficit; hematopoietic stem cell transplantation; longevity; mobilization-based conditioning; mouse.


mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging.

Candice E Van Skike, Ai-Ling Lin, Raquel Roberts Burbank, Jonathan J Halloran, Stephen F Hernandez, James Cuvillier, Vanessa Y Soto, Stacy A Hussong, Jordan B Jahrling, Martin A Javors, Matthew J Hart, Kathleen E Fischer, Steven N Austad, Veronica Galvan.
Aging Cell. 2020 Jan;19(1):e13057. doi: 10.1111/acel.13057. Epub 2019 Nov 6.

Abstract:

Cerebrovascular dysfunction and cognitive decline are highly prevalent in aging, but the mechanisms underlying these impairments are unclear. Cerebral blood flow decreases with aging and is one of the earliest events in the pathogenesis of Alzheimer’s disease (AD). We have previously shown that the mechanistic/mammalian target of rapamycin (mTOR) drives disease progression in mouse models of AD and in models of cognitive impairment associated with atherosclerosis, closely recapitulating vascular cognitive impairment. In the present studies, we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats. Using behavioral tools and MRI-based functional imaging, together with biochemical and immunohistochemical approaches, we demonstrate that chronic mTOR attenuation with rapamycin ameliorates deficits in learning and memory, prevents neurovascular uncoupling, and restores cerebral perfusion in aged rats. Additionally, morphometric and biochemical analyses of hippocampus and cortex revealed that mTOR drives age-related declines in synaptic and vascular density during aging. These data indicate that in addition to mediating AD-like cognitive and cerebrovascular deficits in models of AD and atherosclerosis, mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging. Thus, inhibitors of mTOR may have potential to treat age-related cerebrovascular dysfunction and cognitive decline. Since treatment of age-related cerebrovascular dysfunction in older adults is expected to prevent further deterioration of cerebral perfusion, recently identified as a biomarker for the very early (preclinical) stages of AD, mTOR attenuation may potentially block the initiation and progression of AD.

Keywords: aging; brain vasculature; cerebral blood flow; cognitive decline; functional MRI; mTOR.