Mitochondrial dynamics, biogenesis, and function are coordinated with the cell cycle by APC/C CDH1.

Cell proliferation is associated with a high rate of aerobic glycolysis, which has been widely interpreted as a compensatory mechanism for suppressed mitochondrial function, despite reports of high respiration rates. The molecular mechanisms that link cell proliferation with mitochondrial metabolism, dynamics, and biogenesis remain obscure. Here, we show that proliferation is associated with an increase in both glycolysis and respiration, in conjunction with mitochondrial fusion and biogenesis. Changes in mitochondrial morphology and mass are due to accumulation of OPA1, MFN1, and TFAM, silencing any of which hinders cell proliferation. Moreover, the levels of OPA1, MFN1, and TFAM are regulated by the ubiquitin ligase APC/C(CDH1), which also controls proteasomal degradation of key glycolytic, glutaminolytic, and cell-cycle proteins. Thus, we have identified an important component of the molecular mechanism that coordinates cell proliferation with activation of the mitochondrial metabolic machinery that provides the necessary energy and biosynthetic substrates.

Influence of inositol pyrophosphates on cellular energy dynamics.

With its high-energy phosphate bonds, adenosine triphosphate (ATP) is the main intracellular energy carrier. It also functions in most signaling pathways, as a phosphate donor or a precursor for cyclic adenosine monophosphate. We show here that inositol pyrophosphates participate in the control of intracellular ATP concentration. Yeasts devoid of inositol pyrophosphates have dysfunctional mitochondria but, paradoxically, contain four times as much ATP because of increased glycolysis. We demonstrate that inositol pyrophosphates control the activity of the major glycolytic transcription factor GCR1. Thus, inositol pyrophosphates regulate ATP concentration by altering the glycolytic/mitochondrial metabolic ratio. Metabolic reprogramming through inositol pyrophosphates is an evolutionary conserved mechanism that is also preserved in mammalian systems.

Respiratory response of malignant and placental cells to changes in oxygen concentration.

Malignant cells and foetal tissues are exposed to low oxygen partial pressure (pO2) in situ due to the limited supply of oxygenated blood. Whether these cells have adapted to low pO2 or live under constant constraint is not clear. Herein, we compared the respiratory responses of different malignant cell types, maternal and foetal placental leucocytes, and benign cells by incubating them under a gradient of pO2, from saturation to hypoxia, in a high resolution respirometer. The malignant cells and foetal leucocytes showed higher rates of mitochondrial oxygen uptake compared to the benign cells and maternal leucocytes, respectively. On the other hand, the mitochondrial oxygen uptake rates of the hypoxia adapted cells declined faster than the other cell types during the onset of hypoxia, probably suggesting conformance of aerobic metabolism to the local oxygen concentration. The O2 consumption rate per million cells (JO2) of the malignant cells declined only when the O2 concentration ([O2]) decreased to values

Mitochondrial dysfunction and HIF1alpha stabilization in inflammation.

Activation of murine-derived J774.A1 macrophages with interferon gamma and lipopolysaccharide leads to a progressive mitochondrial defect characterized by inhibition of oxygen consumption and a decrease in the generation of ATP by oxidative phosphorylation. These changes are dependent on the generation of nitric oxide (NO) by an inducible NO synthase that becomes a significant consumer of oxygen. Furthermore, in these activated cells there is a biphasic stabilization of the hypoxia-inducible factor HIF1alpha, the second phase of which is also dependent on the presence of NO. The mitochondrial defect and stabilization of HIF1alpha synergize to activate glycolysis, which, at its maximum, generates quantities of ATP greater than those produced by non-activated cells. Nevertheless, the amount of ATP generated is not sufficient to fulfil the energy requirements of the activated cells, probably leading to a progressive energy deficit with the consequent inhibition of cell proliferation and death.