Subcellular Energetics and Metabolism: A Cross-Species Framework

Abstract

Although it is generally believed that oxidative phosphorylation and adequate oxygenation are essential for life, human development occurs in a profoundly hypoxic environment and "normal" levels of oxygen during embryogenesis are even harmful. The ability of embryos not only to survive but also to thrive in such an environment is made possible by adaptations related to metabolic pathways. Similarly, cancerous cells are able not only to survive but also to grow and spread in environments that would typically be fatal for healthy adult cells. Many biological states, both normal and pathological, share underlying similarities related to metabolism, the electron transport chain, and reactive species. The purpose of Part I of this review is to review the similarities among embryogenesis, mammalian adaptions to hypoxia (primarily driven by hypoxia-inducible factor-1), ischemia-reperfusion injury (and its relationship with reactive oxygen species), hibernation, diving animals, cancer, and sepsis, with a particular focus on the common characteristics that allow cells and organisms to survive in these states.

Figure 1

Thirteen-somite embryo cultured at 40% O₂, demonstrating broad opening of the forebrain (abnormal cranial fold) as compared to embryos cultured at 5% O₂.

Figure 2

During development, cells are exposed to varying levels of O₂, which influences their differentiation.

Figure 3

Interaction of electron transport chain (ETC) with intermediates (FADH₂, NADH). Note that electrons may be ejected from the ETC prematurely, combining with oxygen to produce reactive oxygen species (ROS, e.g. superoxide) and reactive nitrogenous species (RNS, e.g. peroxynitrate), which can subsequently inhibit various components of the ETC. Also note that conversion of pyruvate to lactate, as opposed to Acetyl-CoA, deprives the TCA cycle of substrate, preventing the formation of FADH₂ and NADH and thus the transfer of electrons to the ETC.

Figure 4

HIF-1 and HIF-2 activate thousands of genes, many of which impact metabolism and are protective in the setting of hypoxia.

Figure 5

cancerous cells often live in a hypoxic environment. Their ability to survive, and in some cases thrive, is due to upregulation of a variety of HIF-1 mediated genes that modify metabolism, inhibit apoptosis, induce angiogenesis, and promote invasion and/or metastasis.

Figure 6

Sepsis may be best conceptualized in terms of three distinct strata - the macrovasculature (blood pressure, cardiac output, hemoglobin concentration, arterial oxygen saturation, mixed venous oxygen saturation), the microvasculature, and the subcellular apparatus (mitochondria and electron transport chain, reactive species).