Proteomic profiling of aging in the mouse heart: Altered expression of mitochondrial proteins

Chakravarti, Bulbul; Oseguera, M. A. Perez; Dalal, Neville; Fathy, Pamela; Mallik, Buddhadeb; Raval, Alpan; Chakravarti, Deb N.

doi:10.1016/j.abb.2008.02.001

Cited by 40 publications

(41 citation statements)

References 29 publications

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“…Collectively, these changes can be interpreted as an increase in protein damage with age being counterbalanced by diminished protein synthesis and inadequate PQC. Similar changes in proteostasis have been reported for mammals; aged mice show decreased levels of mitochondrial proteins, proteins involved in defence against oxidative stress, and chaperones involved in the stress response [60][61][62] . In addition, ageing of human der mal fibroblasts ex vivo is also associated with reduced levels of chaperone, proteasomal, ribosomal, and mitochondrial proteins 22 .…”

Section: Derailment During Normal Ageingsupporting

confidence: 72%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

141

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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Section: Derailment During Normal Ageingsupporting

confidence: 72%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

141

126

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“…A proteomic analysis of the whole heart in 19-22 weeks and 24 months old C57BL/6 mice (Chakravarti et al, 2008) based on Comassie-stained 2D gel spot analysis combined with nano-LC-MS-MS characterised 5 up-regulated and 27 down-regulated protein spots. In total 18 spots contained mitochondrial proteins mainly involved in metabolism (pyruvate dehydrogenase, TCA cycle, and fatty acid ␤-oxidation) as well as OXPHOS again indicating an energy-stressed aged heart.…”

Section: Heartmentioning

confidence: 99%

Proteome analysis in the assessment of ageing

Nkuipou‐Kenfack

Koeck

Mischak

et al. 2014

Ageing Research Reviews

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“…The decline in cardiac function with age is associated with changes in mitochondrial function and energy metabolism (Abu-Erreish et al, 1977; McMillin et al, 1993; Fannin et al, 1999; Kates et al, 2003; Bhashyam et al, 2007; Chakravarti et al, 2008). Since the myocardium derives nearly all of its energetic needs from the oxidation of pyruvate and fatty acids within the mitochondria, mitochondrial changes have great potential to contribute to cardiac dysfunction with age.…”

Section: Introductionmentioning

confidence: 99%

“…Since the myocardium derives nearly all of its energetic needs from the oxidation of pyruvate and fatty acids within the mitochondria, mitochondrial changes have great potential to contribute to cardiac dysfunction with age. Indeed, mitochondrial energetic deficiency with aging has been well-documented (McMillin et al, 1993; Fannin et al, 1999; Phaneuf and Leeuwenburgh, 2002; Chakravarti et al, 2008; Ventura-Clapier et al, 2008). The mechanisms of this mitochondrial dysfunction may include biogenesis that is inadequate to match the increasing demand (Goffart et al, 2004), as well as increased mitochondrial uncoupling and decreased substrate availability (Murray et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial and Metabolic Gene Expression in the Aged Rat Heart

et al. 2016

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Aging is associated with a decline in cardiac function. Exercise intervention has been suggested as a way to improve this decrement. Age-related decline in cardiac function is associated with decreases in fatty acid oxidation, mitochondrial function, and AMP-activated protein kinase (AMPK) activity. The molecular mechanisms involved with age-related changes in mitochondrial function and substrate metabolism are poorly understood. We determined gene expression differences in hearts of Young (6 mo), Old (33 mo), and old exercise trained (Old + EXE) (34 mo) FBN rats, using Qiagen PCR arrays for Glucose, Fatty acid, and Mitochondrial metabolism. Old rats demonstrated decreased (p < 0.05) expression for key genes in fatty acid oxidation, mitochondrial function, and AMPK signaling. There were no differences in the expression of genes involved in glucose metabolism with age. These gene expression changes occurred prior to altered protein translation as we found no differences in the protein content of peroxisome proliferator activated receptor gamma, coactivators 1 alpha (PGC-1α), peroxisome proliferator activated receptor alpha (PPARα), and AMPKα 2 between young and old hearts. Four months of exercise training did not attenuate the decline in the gene expression in aged hearts. Despite this lack of change in gene expression, exercise-trained rats demonstrated increased exercise capacity compared to their sedentary counterparts. Taken together, our results show that differential expression of genes associated with fatty acid metabolism, AMPK signaling and mitochondrial function decrease in the aging heart which may play a role in age-related declines in fatty acid oxidation, AMPK activity, and mitochondrial function in the heart.

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Proteomic profiling of aging in the mouse heart: Altered expression of mitochondrial proteins

Cited by 40 publications

References 29 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

Proteome analysis in the assessment of ageing

Mitochondrial and Metabolic Gene Expression in the Aged Rat Heart

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