Mitochondria and oxygen homeostasis, 2022, Mori, Hwang et al.

SNT Gatchaman · Jul 30, 2023

Mitochondria and oxygen homeostasis
Mateus P. Mori; Rozhin Penjweini; Jay R. Knutson; Ping-yuan Wang; Paul M. Hwang

Molecular oxygen possesses a dual nature due to its highly reactive free radical property: it is capable of oxidizing metabolic substrates to generate cellular energy, but can also serve as a substrate for genotoxic reactive oxygen species generation. As a labile substance upon which aerobic life depends, the mechanisms for handling cellular oxygen have been ﬁne-tuned and orchestrated in evolution. Protection from atmospheric oxygen toxicity as originally posited by the Endosymbiotic Theory of the Mitochondrion is likely to be one basic principle underlying oxygen homeostasis.

We brieﬂy review the literature on oxygen homeostasis both in vitro and in vivo with a focus on the role of the mitochondrion where the majority of cellular oxygen is consumed. The insights gleaned from these basic mechanisms are likely to be important for understanding disease pathogenesis and developing strategies for maintaining health.

Link | PDF (The FEBS Journal)

Hutan · Jul 30, 2023

Such exercise-induced hypoxia demonstrates the extremes of supply-demand mismatch caused by mitochondrial oxygen consumption, which can increase over 100-fold during physical exercise [[19]].
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Given these in vivo observations, physioxia cannot be assigned standard values that apply to all tissues under all conditions. Rather, factors such as tissue vascularization, blood flow, and oxygen consumption rate—as well as other determinants such as animal species, functional state, tissue architecture, size of the organ, and even distance from the heart—should be taken into consideration to determine physioxia.
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I wonder if a state of hypoxia, perhaps even just normal levels of hypoxia, could be the trigger for an abnormal process that results in PEM?

Hutan · Jul 30, 2023

Metabolically, Mb−/− perfused hearts showed higher lactate utilization and a shift from predominantly fatty acid oxidation to glycolysis, further indicating the activation of compensatory metabolic processes [[25, 27]]. This shift was also accompanied by decreased expression of β-oxidation pathway genes and an increase in the active form of glucose transporter GLUT4 involved in glucose utilization [[27]]. Although myoglobin is nonessential for the survival of laboratory-bred mice, the relatively small decreases in aerobic metabolism and endurance exercise capacity in the myoglobin-deficient state cannot be disregarded as the magnitude of changes that permit successful adaptation of an organism in evolution can be very small [[28]].
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Morphologically, an innovative study of mouse skeletal muscle revealed a reticular network of paravascular (PV) mitochondria adjacent to capillary vessels that were physically and electrically coupled to mitochondria in the intrafibrillar region [[29]]. Remarkably, the ratio of mitochondrial respiratory complex IV (cytochrome c oxidase) to complex V (ATPase) in PV mitochondria, presumably with better access to O2 via the capillaries, was higher compared with that of intrafibrillar mitochondria. One possible interpretation of this observation is that PV mitochondria are specialized to generate the proton-motive force by active respiration due to their proximity to oxygen-rich capillaries, while the intrafibrillar mitochondria produce the ATP at the site of their utilization by the contractile apparatus, supporting the original concept of mitochondria as energy-transmitting cables [[30]].
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Although these in vitro data do not rule out other possible mechanisms of HIF-1α stabilization, they fit with the well-known observation of exercise-induced hypoxia in skeletal muscle, which associates with acute HIF-1α stabilization and activation of VEGF and EPOgenes in the human vastus lateralis thigh muscle after exercise [[33]].
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Hutan · Jul 30, 2023

Measurement of oxygen levels in cells

While there is evidence that alterations in cellular O2 homeostasis can affect in vivometabolism, there has been substantial controversy regarding O2 levels and the existence of O2 gradients within the cellular microenvironment due to the lack of appropriate intracellular probes [[34, 35]]. The recent development of optical probes sensitive to molecular oxygen has permitted in vitro measurements at the cellular level (although these data need to be interpreted with caution given the various limitations of O2 delivery in the tissue culture geometry setting) [[36, 37]]. Nonetheless, under controlled conditions, these techniques can serve as powerful tools for investigating the effects of mitochondrial respiration on cellular O2 homeostasis and for developing insights into their in vivosignificance.
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Hutan · Jul 30, 2023

Given the preponderance of evidence that mitochondrial respiration in vivo affects O2homeostasis, the question arises as to whether increases in tissue O2 levels due to its decreased consumption in mitochondrial diseases, for example, can cause toxicity.
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There's discussion of the negative effects of increased levels of oxygen. The low oxygen environment of high altitudes seems to protect against cancers. Oxygen supplementation in the absence of evidence of hypoxia does not seem to help improve patient outcomes in stroke and heart attack. That suggests that being exposed to high levels of oxygen on a regular basis might do more harm than good.

There is broad acceptance that mitochondria are the major source of cellular ROS, but the evidence provided in this review suggests that mitochondrial deficiency states may result in even greater O2 toxicities. While there are evidence that ROS generated at low levels have physiological functions [[72, 73]], the mitochondria being the main source of damaging ROS is more debatable [[41, 74-76]]. A critical factor in this controversy is the availability of O2 as a substrate for ROS generation at the level of the mitochondrial enzymes in vivo, which the aforementioned study of Penjweini et al finds is lower than that in the cytosol—adding support to prior proposals of the mitochondrion as an oxygen sink
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The paper casts doubt on the idea of mitochondria producing problematic levels of reaction oxygen species (ROS).

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