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Changes in calcium wave patterns show that an active TR lacking its DNA-binding domain (bottom) stimulates mitochondrial activity.

The body often responds to increased energy demands during growth or development by secreting thyroid hormone. Activated thyroid hormone receptors (TRs) increase long-term mitochondrial output through transcriptional changes. But on page 915, Saelim et al. show that some TRs supersede transcription to cause rapid, transient changes in mitochondrial function.

The fast-acting TRs were those that were targeted to mitochondria rather than to the nucleus. Using frog oocytes, which lack their own TRs, the authors show that mitochondrial TRs energize respiration in response to thyroid hormone. These TRs did not require either their DNA-binding domains or transcriptional activities.

How respiration was initially jump-started is not clear, but the mitochondria consumed more oxygen and had increased membrane potentials when mitochondrial TRs were activated. Presumably as a result of this increased potential, passive Ca²⁺ uptake was stimulated, as seen by the ability of mitochondria to influence Ca²⁺ release from the ER.

A rapid, transient rise in mitochondrial respiration could serve several functions in the cell. First, the increase in mitochondrial Ca²⁺ is likely to ramp up ATP production, as several enzymes in the citric acid cycle are Ca²⁺ dependent. This might provide a temporary energy boost to tide cells over until the hormone's transcriptional effects lead to more mitochondria.

Second, increased mitochondrial Ca²⁺ sequestration will reduce cytosolic Ca²⁺ levels, thereby inhibiting Ca²⁺-dependent processes in the cytosol. Finally, the ability to activate rapidly the ability of mitochondria to take in Ca²⁺ might be beneficial under conditions of cell stress or hypoxia. Stress-related cytoplasmic Ca²⁺ spikes can have deleterious effects, including cell death. Limiting the damage caused by high Ca²⁺ loads by the specific activation of mitochondrial TRs might be one way to curb neuronal death after a stroke.

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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Related Article

Nontranscriptional modulation of intracellular Ca²⁺ signaling by ligand stimulated thyroid hormone receptor

Nuttawut Saelim, Linu M. John, Jun Wu, Jeong Soon Park, Yidong Bai, Patricia Camacho, and James D. Lechleiter
J. Cell Biol. 2004 167: 915-924. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 641K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Related Collections Related Article Social Bookmarking                            What's this?