Mitochondrial Proteins

Publication Title: 
Antioxidants & Redox Signaling

SIGNIFICANCE: Among the most highly investigated theories of aging is the mitochondrial theory of aging. The basis of this theory includes a central role for altered or compromised mitochondrial function in the pathophysiologic declines associated with aging. In general, studies in various organisms, including nematodes, rodents, and humans, have largely upheld that aging is associated with mitochondrial dysfunction.

Author(s): 
Pulliam, Daniel A.
Bhattacharya, Arunabh
Van Remmen, Holly
Publication Title: 
PloS One

The immune response is essential for survival by destroying microorganisms and pre-cancerous cells. However, inflammation, one aspect of this response, can result in short- and long-term deleterious side-effects. Mclk1?/? mutant mice can be long-lived despite displaying a hair-trigger inflammatory response and chronically activated macrophages as a result of high mitochondrial ROS generation. Here we ask whether this phenotype is beneficial or simply tolerated. We used models of infection by Salmonella serovars and found that Mclk1?/?

Author(s): 
Wang, Dantong
Wang, Ying
Argyriou, Catherine
CarriËre, Audrey
Malo, Danielle
Hekimi, Siegfried
Publication Title: 
The International Journal of Biochemistry & Cell Biology

Calorie-restricted feeding retards the rate of ageing in mammalian and invertebrate species. The molecular mechanisms underlying this effect include a lower rate of accrual of tissue oxidative damage that is associated with a significantly lower rate of mitochondrial free radical generation in rodent species. To identify the important sites of control and regulation for mitochondrial free radical generation during ageing and calorie-restricted feeding, metabolic control analysis is being applied to the study of mitochondrial bioenergetics.

Author(s): 
Merry, B. J.
Publication Title: 
Aging Cell

Loss of nonshivering thermogenesis in mice by inactivation of the mitochondrial uncoupling protein gene (Ucp1-/- mice) causes increased sensitivity to cold and unexpected resistance to diet-induced obesity at a young age. To clarify the role of UCP1 in body weight regulation throughout life and influence of UCP1 deficiency on longevity, we longitudinally analyzed the phenotypes of Ucp1-/- mice maintained in a room at 23 degrees C.

Author(s): 
Kontani, Y.
Wang, Y.
Kimura, K.
Inokuma, K.-I.
Saito, M.
Suzuki-Miura, T.
Wang, Z.
Sato, Y.
Mori, N.
Yamashita, H.
Publication Title: 
Experimental Gerontology

The clk-1 gene of the nematode Caenorhabditis elegans encodes an evolutionarily conserved enzyme that is necessary for ubiquinone biosynthesis. Loss-of-function mutations in clk-1, as well as in its mouse orthologue mclk1, increase lifespan in both organisms. In nematodes, clk-1 extends lifespan by a mechanism that is distinct from the insulin signaling-like pathway but might have similarities to calorie restriction. The evolutionary conservation of the effect of clk-1/mclk1 on lifespan suggests that the gene affects a fundamental mechanism of aging.

Author(s): 
Stepanyan, Zaruhi
Hughes, Bryan
Cliche, Dominic O.
Camp, Darius
Hekimi, Siegfried
Publication Title: 
Cell Metabolism

Age-related disease, not aging per se, causes most morbidity in older humans. Here we report that skeletal muscle respiratory uncoupling due to UCP1 expression diminishes age-related disease in three mouse models. In a longevity study, median survival was increased in UCP mice (animals with skeletal muscle-specific UCP1 expression), and lymphoma was detected less frequently in UCP female mice. In apoE null mice, a vascular disease model, diet-induced atherosclerosis was decreased in UCP animals.

Author(s): 
Gates, Allison C.
Bernal-Mizrachi, Carlos
Chinault, Sharon L.
Feng, Chu
Schneider, Jochen G.
Coleman, Trey
Malone, James P.
Townsend, R. Reid
Chakravarthy, Manu V.
Semenkovich, Clay F.
Publication Title: 
Current Aging Science

The discovery of novel uncoupling proteins (UCP2 and UCP3) over 10 years ago heralded a new era of research in mitochondrial uncoupling in a diverse range of tissues. Despite the research vigor, debate stills surrounds the exact function of these uncoupling proteins. For example, the level of uncoupling, the mechanism and mode of action are all under-appreciated at this point in time. Our recent work has used genetic mouse models to focus on the physiological relevance of UCP2. We have used these mouse models to better appreciate the role UCP2 in human health and disease.

Author(s): 
Andrews, Zane B.
Publication Title: 
Mechanisms of Ageing and Development

The quest to understand why we age has given rise to numerous lines of investigation that have gradually converged to include metabolic control by mitochondrial activity as a major player. That is, the ideal balance between nutrient uptake, its transduction into usable energy, and the mitigation of damaging byproducts can be regulated by mitochondrial respiration and output (ATP, reactive oxygen species (ROS), and heat). Mitochondrial inefficiency through proton leak, which uncouples substrate oxidation from ADP phosphorylation, can comprise as much as 30% of the basal metabolic rate.

Author(s): 
Mookerjee, Shona A.
Divakaruni, Ajit S.
Jastroch, Martin
Brand, Martin D.
Publication Title: 
Amino Acids

Maillard reaction contributes to the chemical modification and cross-linking of proteins. This process plays a significant role in the aging process and determination of animal longevity. Oxidative conditions promote the Maillard reaction. Mitochondria are the primary site of oxidants due to the reactive molecular species production. Mitochondrial proteome cysteine residues are targets of oxidative attack due to their specific chemistry and localization. Their chemical, non-enzymatic modification leads to dysfunctional proteins, which entail cellular senescence and organismal aging.

Author(s): 
Naudí, Alba
Jové, Mariona
Cacabelos, Daniel
Ayala, Victoria
Cabre, Rosanna
Caro, Pilar
Gomez, JosÈ
Portero-Otín, Manuel
Barja, Gustavo
Pamplona, Reinald
Publication Title: 
Molecular & cellular proteomics: MCP

Calorie restriction (CR) promotes longevity. A prevalent mechanistic hypothesis explaining this effect suggests that protein degradation, including mitochondrial autophagy, is increased with CR, removing damaged proteins and improving cellular fitness. At steady state, increased catabolism must be balanced by increasing mitochondrial biogenesis and protein synthesis, resulting in faster protein replacement rates.

Author(s): 
Price, John C.
Khambatta, Cyrus F.
Li, Kelvin W.
Bruss, Matthew D.
Shankaran, Mahalakshmi
Dalidd, Marcy
Floreani, Nicholas A.
Roberts, Lindsay S.
Turner, Scott M.
Holmes, William E.
Hellerstein, Marc K.

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