Functional Mitochondria Are Important for the Effect of Resveratrol.

Resveratrol (Resv) is a polyphenol reported to modulate mitochondrial activity. The aim was to use HeLa and 143B cells to characterize the action of Resv on mitochondrial activity, cell size and proliferation using wild type (WT) and Rho 0 cells deficient in mitochondrial DNA. In both HeLa WT and Rho 0 cells, the oxygen consumption rate (OCR) was increased at 20 µM Resv after 24 h, whereas only a non-significant increase of OCR was observed in 143B WT cells. Resv decreased cell number concentration-dependently in both WT and Rho 0 cell types. An increased cell diameter was observed in HeLa WT, but not in Rho 0 when treated with Resv. Overall, the findings presented indicate that functional mitochondria are a prerequisite for cell enlargement by Resv.

mTOR: more targets of resveratrol?

Resveratrol (RSV) is a natural polyphenol produced by plants and is proposed to have multiple beneficial effects on health. In recent years, the interest in this molecule has increased nearly exponentially following the major findings that RSV (I) is chemo-preventive in some cancer models, (II) is cardio-protective and (III) has positive effects on metabolism in mammals and increases lifespan in lower organisms. Mechanistic target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism and angiogenesis. As a part of the mTORC1 and mTORC2 complexes, the mTOR kinase plays a key role in several pathways involved in cancer and metabolic diseases. Recent studies suggest that modulation of the mTOR signalling pathway could play an important role in mediating the beneficial effects of RSV. Therefore, this review summarises the current findings regarding RSV and its inhibition/activation of the proteins in the mTOR pathway, and thereby propose the proteins of the mTOR cascade to be primary targets for RSV. RSV affects many different targets related to mTOR, and it is not clear which is most relevant. However, most frequently, RSV is found to inhibit the activity of the mTOR pathway proteins, and to activate AMPK and LKB1, which can suppress mTOR signalling. Thus, it appears that RSV plays a role in modulation of proteins of the mTOR pathway although more research is still needed to fully understand the interaction.

Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance.

Rapamycin extends lifespan in mice, but can have a number of undesirable effects that may ultimately limit its utility in humans. The canonical target of rapamycin, and the one thought to account for its effects on lifespan, is the mammalian/mechanistic target of rapamycin, complex 1 (mTORC1). We have previously shown that at least some of the detrimental side effects of rapamycin are due to "off target" disruption of mTORC2, suggesting they could be avoided by more specific targeting of mTORC1. However, mTORC1 inhibitionper se can reduce the mRNA expression of mitochondrial genes and compromise the function of mitochondria in cultured muscle cells, implying that defects in bioenergetics might be an unavoidable consequence of targeting mTORC1 in vivo. Therefore, we tested whether rapamycin, at the same doses used to extend lifespan, affects mitochondrial function in skeletal muscle. While mitochondrial transcripts were decreased, particularly in the highly oxidative soleus muscle, we found no consistent change in mitochondrial DNA or protein levels. In agreement with the lack of change in mitochondrial components, rapamycin-treated mice had endurance equivalent to that of untreated controls, and isolated, permeabilized muscle fibers displayed similar rates of oxygen consumption. We conclude that the doses of rapamycin required to extend life do not cause overt mitochondrial dysfunction in skeletal muscle.