Sci. Aging Knowl. Environ., 16 April 2003
Vol. 2003, Issue 15, p. nw58
[DOI: 10.1126/sageke.2003.15.nw58]


Losing StAR Power

Oxidants thwart testosterone production by barring crucial transporter from mitochondria

Mary Beckman;2003/15/nw58

Key Words: steroidogenesis • cyclic AMP • membrane potential

Years of battering by metabolic byproducts might render a cellular site that contributes to testosterone output incapable of supporting the hormone's production, according to new work. A protein that's essential for manufacturing a key hormone precursor can't slip into injured production facilities--mitochondria--in testes, the research indicates. The results suggest why the sex hormone dwindles as men age.

Like women, men experience a decline in sex hormone production beginning at around age 40, although the so-called andropause proceeds slowly, unlike menopause's plunge. In testes, Leydig cells--the site of testosterone synthesis--gradually stop working. Scientists know that reactive oxygen species (ROS)--byproducts of energy production that damage other molecules (see "The Two Faces of Oxygen")--cut testosterone production by causing problems in the Leydig cells' mitochondria, where the first step of sex hormone synthesis occurs. Diemer and colleagues wanted to uncover the molecular details of the manufacturing shutdown.

In Leydig cells, a blood-borne hormone periodically boosts amounts of the signaling molecule cAMP, which stimulates the cell to make steroidogenic acute regulatory (StAR) protein. StAR grabs free cholesterol from the cytoplasm and trucks it into the cell's mitochondria, where another protein, SCC, converts it into a progesterone precursor. In humans, the precursor returns to the cytoplasm, where other enzymes transform it into progesterone and eventually into testosterone.

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The Leydig gig. ROS halt hormone production by bashing up the factory. The key protein is the StAR of the show. [Source: Dale B. Hales; Illustration: Julie White]

The researchers took advantage of Leydig tumor cells that manufacture progesterone but don't complete the biochemical process of making testosterone. They measured the effect of ROS on amounts of StAR in cells that had been activated with cAMP. Quantities of the version of StAR found outside the mitochondria were the same before and after treatment with the ROS hydrogen peroxide. However, amounts of the StAR variety found inside the mitochondria dove to almost nothing after the researchers added ROS, indicating that the protein could not get into the mitochondria of stressed cells.

Much as water that is backed up behind a dam powers electricity generation, hydrogen ions that are stored within healthy mitochondria power production of ATP. To measure how well stressed mitochondria maintain their hydrogen ion reservoir, the researchers added to Leydig cells a dye that colors the ion stash. Sixty minutes of hydrogen peroxide treatment drained the ion reservoir. Taken together, the data suggest that ROS breach the mitochondrial power reservoir, which blocks StAR from entering the mitochondria with cholesterol on its back, says steroid biochemist and co-author Dale B. Hales of the University of Illinois, Chicago. The lack of raw material arrests the production of testosterone, he says.

The research team has found an elegant "mechanism of action for how ROS can decrease testosterone production," says biochemist Douglas Stocco of the Texas Tech University Health Sciences Center in Lubbock, although additional work is needed to show that accumulated mitochondrial damage from ROS causes infertility in aging men. If so, putting StAR center stage might keep the curtain from dropping on male fertility.

--Mary Beckman; suggested by James M. Harper

April 16, 2003
  1. T. Diemer, J. Allen, K. H. Hales, D. B. Hales. Reactive oxygen disrupts mitochondria in MA-10 tumor Leydig cells and inhibits steroidogenic acute regulatory (StAR) protein and steroidogenesis. Endocrinology, 3 April 2003 [e-pub ahead of print]. [Abstract] [Full text]
Citation: M. Beckman, Losing StAR Power. Sci. SAGE KE 2003, nw58 (16 April 2003);2003/15/nw58

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