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Mitochondria01:37

Mitochondria

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Mitochondria are eukaryotic cellular organelles that are known to produce energy through a process called oxidative phosphorylation. Besides their primary function, mitochondria are involved in various cellular processes, including cell growth, differentiation, signaling, metabolism, and senescence. Age-related changes cause a decline in mitochondrial quality and integrity due to increased mitochondrial mutations and oxidative damage. Thus, aging can severely impact mitochondrial functions,...
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A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
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Overview of Metabolism01:40

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Living cells constantly carry out various chemical reactions which are necessary for their proper functioning. These reactions are interlinked to one another via multiple pathways. The collection of these chemical reactions is known as metabolism.
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Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70  chaperones are targetted to TOM20-TOM22 receptor complexes.
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Mitochondrial metabolites extend lifespan.

Robert J Mishur1,2, Maruf Khan1,2, Erin Munkácsy1,3

  • 1The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.

Aging Cell
|January 6, 2016
PubMed
Summary
This summary is machine-generated.

Disrupting mitochondrial respiration and providing specific alpha-ketoacids can extend lifespan in worms by stabilizing hypoxia-inducible factor-1 (HIF-1). This suggests a novel signaling pathway regulating longevity.

Keywords:
Caenorhabditis elegansEGL-9/PHDMit mutantsagingglutaric acidemiahypoxia-inducible factor isp-1hypoxia-inducible factor-1jumonji domain-containingmetabolismmitochondriaα-ketoglutarate-dependent hydroxylases

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Area of Science:

  • Cellular Biology
  • Genetics
  • Aging Research

Background:

  • Mitochondrial respiration dysfunction in Caenorhabditis elegans is linked to lifespan extension.
  • Long-lived respiratory mutants exhibit elevated alpha-ketoacid levels, structurally similar to alpha-ketoglutarate.

Purpose of the Study:

  • To investigate if alpha-ketoacids can extend lifespan in wild-type worms.
  • To elucidate the role of hypoxia-inducible factor-1 (HIF-1) in mediating the lifespan-extending effects of alpha-ketoacids.

Main Methods:

  • Administration of alpha-ketoacids and 2,4-pyridinedicarboxylic acid (2,4-PDA) to wild-type Caenorhabditis elegans.
  • Genetic manipulation to remove HIF-1.
  • Assessment of lifespan extension.
  • Incubation of mouse 3T3-L1 fibroblasts with alpha-ketoacids to observe HIF-1α stabilization.

Main Results:

  • Supplementation with alpha-ketoacids extended the lifespan of wild-type worms.
  • The lifespan extension was mediated, in part, by the stabilization of hypoxia-inducible factor-1 (HIF-1).
  • 2,4-pyridinedicarboxylic acid (2,4-PDA), an alpha-ketoglutarate mimetic, extended lifespan, an effect blocked by HIF-1 removal.
  • 2,4-PDA did not further increase lifespan in mutants with constitutively active HIF-1.
  • Alpha-ketoacids stabilized HIF-1α in mouse fibroblasts.

Conclusions:

  • Metabolites accumulating from mitochondrial dysfunction represent a novel signaling mechanism regulating lifespan.
  • Alpha-ketoacids, potentially acting through HIF-1 stabilization, can promote longevity.
  • This pathway offers new insights into the molecular basis of aging and potential therapeutic targets.