Beyond mitochondria: Alternative energy-producing pathways from all strata of life

Abstract

It is well-established that mitochondria are the powerhouses of the cell, producing adenosine triphosphate (ATP), the universal energy currency. However, the most significant strengths of the electron transport chain (ETC), its intricacy and efficiency, are also its greatest downfalls. A reliance on metal complexes (FeS clusters, hemes), lipid moities such as cardiolipin, and cofactors including alpha-lipoic acid and quinones render oxidative phosphorylation vulnerable to environmental toxins, intracellular reactive oxygen species (ROS) and fluctuations in diet. To that effect, it is of interest to note that temporal disruptions in ETC activity in most organisms are rarely fatal, and often a redundant number of failsafes are in place to permit continued ATP production when needed. Here, we highlight the metabolic reconfigurations discovered in organisms ranging from parasitic Entamoeba to bacteria such as pseudomonads and then complex eukaryotic systems that allow these species to adapt to and occasionally thrive in harsh environments. The overarching aim of this review is to demonstrate the plasticity of metabolic networks and recognize that in times of duress, life finds a way.

Keywords: ATP; Energy; Metabolic reconfiguration; Metabolism; Mitochondrial dysfunction.

Figure 1:

The tricarboxylic acid (TCA) cycle and electron transport chain are vulnerable to environmental stressors. Biomolecular components in red are prone to oxidative damage and degradation. ACN: aconitase; KGDH: α-ketoglutarate dehydrogenase; mtDNA: mitochondrial DNA; PDH: pyruvate dehydrogenase.

Figure 2:

Pyrophosphate-dependent glycolysis harnesses the high-energy bond of PP_i for ATP production. EMP: Embden-Meyerhof-Parnas; HK: hexokinase; PFK: phosphofructokinase; PGK: phosphoglycerate kinase; PK: pyruvate kinase; PPDK: pyruvate phosphate dikinase.

Figure 3:

The glyoxylate shunt allows organisms to circumvent aerobic metabolism when faced with stress. Enzymatic reactions in red are down-regulated, while those in green see increased activity as part of the glyoxylate shunt. ACKA: acetate kinase A; ICDH: isocitrate dehydrogenase; ICL: isocitrate lyase; MS: malate synthase; PTA: phosphotransacetylase; TCA: tricarboxylic acid.

Figure 4:

In higher mammals, hypoxia-inducible factors (HIFs) and heat shock proteins (HSPs) facilitate the shift to anaerobic metabolism. EMP: Embden-Meyerhof-Parnas; FIH: asparagine-targeting factor inhibiting HIF; PEP: phosphoenolpyruvate; PHD: prolyl hydroxylase domain; PK: pyruvate kinase; ROS: reactive oxygen species.

Figure 5:

Mitochondrial substrate level phosphorylation via succinate-CoA ligase (SUCLA2) enables survival despite a defective electron transport chain. GLUD1: glutamate dehydrogenase 1; HIF: hypoxia-inducible factor; KGDH: α-ketoglutarate dehydrogenase.

Figure 6:

Phosphotransfer systems permit the delivery and storage of high-energy phosphate in the form of phosphagens which are conducive to rapid ATP production during a stress response. Cr: creatine; ETC: electron transport chain; HIF: hypoxia-inducible factor; PCr: phosphocreatine.