Review

Mitochondrial dysfunction and longevity in animals: Untangling the knot

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Science  04 Dec 2015:
Vol. 350, Issue 6265, pp. 1204-1207
DOI: 10.1126/science.aac4357

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  • The positively charged hemoglobin leads to long lifespan
    • Qiuyun Liu, Professor, Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Sun Yat-sen University
    • Other Contributors:
      • Jianguo He, Professor, Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Sun Yat-sen University
      • Shaoping Weng, Professor, Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Sun Yat-sen University

    Hemoglobin is a positively charged protein, harboring 16.8% and 15.6% basic amino acids in the alpha and beta subunit respectively (GenBank accession No. NP_000508.1 and NP_000509.1), which attract anions such as chloride ions capable of dissolving insoluble salts such as oxalate. Insoluble and rigid salts are harmful to human, and oxalate may be a death mediator (1-4). However, basic proteins sometimes pose cancer risks when other polymorphisms are also present (5-8). Sodium and potassium in the blood and cells may help neutralize strong acids and thus reduce cancer risks (9). Some other positively charged proteins might share the aforementioned property as hemoglobin.

    Jianguo He, 1,2, Shaoping Weng, 1,2 Qiuyun Liu 1,*
    1. Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Biomedical Center, State Key Laboratory of Biocontrol, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
    2. Equal contribution.

    *Correspondence author.
    E-mail address: lsslqy@mail.sysu.edu.cn (Q. Liu)

    REFERENCES
    1. Y. Shi et al., Science, (2017); http://science.sciencemag.org/content/347/6228/1319/tab-e-letters
    2. Y. Gao et al., Science, (2017); http://scienc...

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    Competing Interests: None declared.
  • Oxalate may be a death mediator
    • Qiuyun Liu, Professor, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, China.
    • Other Contributors:
      • Jianguo He, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
      • Shaoping Weng, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
      • Xingqiang Lai, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.

    Oxalate is implicated in kidney stone and other ailments, and the median lethal doses of oxalate for animals were moderate (1-2), highlighting the detrimental role of oxalate overproduction from the shunt of Krebs cycle and other pathways. A hypothesis is postulated that high content of oxalate leads to the formation of hard insoluble divalent salts, which may cause spasm and death. The rigor mortis can be a manifestation of this process. The collapse of respiratory chain would lead to accumulation of the short chain organic acids via Krebs cycle. Compounds with similar structures to oxalate can be developed to counteract the effects of oxalate. RNA interference may interrupt the formation of oxalate, and thus treating numerous diseases and prolonging lives. The success in animal experiments could lead to effective regimens for extending lifespan, which may also be able to treat numerous human disorders.

    Jianguo He, Shaoping Weng, Xingqiang Lai, Qiuyun Liu*
    State Key Laboratory of Biocontrol, Key Laboratory for Improved Variety Reproduction of Aquatic Economic Animals of Guangdong Province, Biotechnology Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    *Correspondence author.
    E-mail address: lsslqy@mail.sysu.edu.cn (Q. Liu)

    REFERENCES
    1. Y. Gao et al., Science, (2017); htt...

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    Competing Interests: None declared.
  • Organic acids and calorie restriction
    • Qiuyun Liu, Superviser/Writting/Professor, State Key Laboratory of Biocontrol, MOE Key Laboratory of Aquatic Product Safety, Sun Yat-sen University, China
    • Other Contributors:
      • Ye Gao, Writting/Student, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
      • Yan Huang, Writting/Student, Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China
      • Danling Dai, Writting/Student, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
      • Xiaoxuan Wu, Writting/Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Wei Yang, Writting/Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    The mortality rates in cold winter times are higher than those in other seasons (1-2), and joints are stiff at freezing temperatures. Footballers often have leg spasm after extensive running, and dozens of marathon runners died each year when they were mid-way through or near the finishing lines (3-4). What do these phenomena have in common? A dietary regimen known as Calorie restriction (CR) has been reported to delay the biological aging process, resulting in extension in lifespan (5). Krebs cycle is one of the major sources of organic acids. Oxalic acid was described to be an important virulence factor produced by phytopathogenic filamentous fungi (6). Acute renal failure was reported following oxalate ingestion (7-8). The median lethal doses (LD50) of oxalate for animals are moderate (9), and an intravenous dose of 1.2 grams of sodium oxalate was fatal in a documented human case (10). Based on the oral LD50 value of 375 mg/kg in rats, uptake of about 22 grams of oxalic acid could be fatal to a 59 kg or less human (11). Oxalate forms insoluble salts with numerous metal ions. Oxalate analogues such as ethanol, acetic acid could extend lifespan after moderate intake (12-13). Some other short chain organic acids such as citrate and malate also form insoluble calcium salts and have a modest median lethal doses on animals. It may shed light on the mechanism of lifespan extension by calorie restriction.
    Physical exercises in normal people might channel energy metabolis...

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    Competing Interests: None declared.
  • Mitochondria in aging: untangling cause and effect
    • David Bargiela, Postdoctoral researcher (Neurology), Brigham & Women's Hospital/ Harvard Medical School

    In their review "Mitochondrial dysfunction and longevity in animals: Untangling the knot" (4 December 2015, p.1204), Wang et al. challenge the mitochondrial free-radical theory of aging and provide an engaging overview of the contrasting role of mitochondrial reactive oxygen species (ROS) in promoting longevity.

    Mitochondria-generated ROS have been studied in a range of organisms with strikingly diverse effects on aging and cell signalling noted, in part dependent on the subcellular compartment in which they accumulate (1). The authors’ conclusion that “…neither chronic nor acutely severe mitochondrial dysfunction is sufficient to produce irreversible phenotypes that limit lifespan.” appears to draw the enquiry into their effects on aging to a premature close. The reality, however, is the evidence required to confidently support such a bold statement is currently insufficient – we simply don’t know enough about the downstream cascades following ROS level perturbation that can result in opposing phenotypes.

    Moreover, it is worth considering the wider context by which mitochondrial dysfunction may impact longevity, via ROS-independent mechanisms. Complex interventions that extend lifespan, such as calorie restriction, affect mitochondrial turnover through induction of transcriptional regulators (2, 3). Similarly, telomere dysfunction, a well-established cellular processes associated with aging, results in alteration to the structure and function of m...

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    Competing Interests: None declared.