Asymptomatic Hypoxemia as a Characteristic Symptom of Coronavirus Disease: A Narrative Review of Its Pathophysiology

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic and caused a huge burden to healthcare systems worldwide. One of the characteristic symptoms of COVID-19 is asymptomatic hypoxemia, also called happy hypoxia, silent hypoxemia, or asymptomatic hypoxemia. Patients with asymptomatic hypoxemia often have no subjective symptoms, such as dyspnea, even though hypoxemia is judged by objective tests, such as blood gas analysis and pulse oximetry. Asymptomatic hypoxemia can lead to acute respiratory distress syndrome, and the delay in making a diagnosis and providing initial treatment can have fatal outcomes, especially during the COVID-19 pandemic. Thus far, not many studies have covered asymptomatic hypoxemia. We present a review on the human response to hypoxemia, focusing on the respiratory response to hypoxemia rather than the pathophysiology of lung injury arising from SARS-CoV-2 infection. We have also discussed whether asymptomatic hypoxemia is specific to SARS-CoV-2 infection or a common phenomenon in lung-targeted viral infections.

Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival

Endoplasmic reticulum stress (ERS) occurs when cellular demand for protein folding exceeds the capacity of the organelle. Adaptation and cell survival in response to ERS requires a critical contribution by mitochondria and peroxisomes. During ERS response, mitochondrial respiration increases to ameliorate reactive oxygen species (ROS) accumulation; we now show in yeast that peroxisome abundance also increases to promote an adaptive response. In pox1▵ cells, defective in peroxisomal ß oxidation of fatty acids, respiratory response to ERS is impaired, and ROS accrues. However, respiratory response to ERS is rescued, and ROS production is mitigated in pox1▵ cells by overexpression of Mpc1, the mitochondrial pyruvate carrier that provides another source of acetyl CoA to fuel the TCA cycle and oxidative phosphorylation. Using proteomics, select mitochondrial proteins were identified that undergo upregulation by ERS to remodel respiratory machinery. Several peroxisome-based proteins were also increased, corroborating the peroxisomal role in ERS adaptation. Finally, ERS stimulates assembly of respiratory complexes into higher order supercomplexes, underlying increased electron transfer efficiency. Our results highlight peroxisomal and mitochondrial support for ERS adaptation to favor cell survival.

Beyond the acute phase: understanding relationships among cardio-respiratory response to exercises, physical activity levels, and quality of life in children after burn injuries

The long-term cardiorespiratory function in burn-injured children can be jeopardized due to complications brought on by the injury. This study sought to assess the cardio-respiratory responses to maximal exercise in children who sustained a burn injury and explore the relationships among cardio-respiratory response, physical activity levels (PALs), and health-related quality of life (HRQL). Forty-five burn-injured children (age:13.89±2.43 years; duration since burn-injury: 3.13±0.93 years) and 52 age- and gender-matched healthy children (14.15±2.27 years) participated in this study. Both cohorts were evaluated for the maximal exercise capacity [defined by peak oxygen uptake (VO2peak), maximum heart rate (HRmax), minute ventilation (VE), ventilatory equivalent (VEq), respiratory rate (RR), and respiratory exchange ratio (RER)], PALs, and HRQL. The burn-injured children had significantly lower VO2peak (P=.0001) and VE (P=.003) and higher VEq (P<.0001) and RR (P=.007) than their healthy controls, indicating less efficient cardio-respiratory capacity. However, the HRmax (P=.092) and RER (P=.251) were similar. The burn-injured children reported significantly lower PALs (P=.014) and HRQL (P<.0001). The PALs [r (95%CI) = 0.411 (0.132 to 0.624); P = .005] and HRQL [r (95%CI) = 0.536 (0.284 to 0.712); P = .0001] were significantly correlated with the cardio-respiratory capacity represented by VO2peak in burn-injured group. The variations in VO2peak explained ⁓ 17% and 28.7% of the variations in PALs and HRQL, respectively. In conclusion, the cardio-respiratory efficiency of the burn-injured children may remain limited, even up to a few years following the injury. The limited cardio-respiratory capacity account in part for the reduced PALs and HRQL.

Dark respiration rates are not determined by differences in mitochondrial capacity, abundance and ultrastructure in C4 leaves

Our understanding of the regulation of respiration in C plants, where mitochondria play different roles in the different types of C photosynthetic pathway, remains limited. We examined how leaf dark respiration rates (R), in the presence and absence of added malate, vary in monocots representing the three classical biochemical types of C photosynthesis (NADP-ME, NAD-ME and PCK) using intact leaves and extracted bundle sheath strands. In particular, we explored to what extent R are associated with mitochondrial number, volume and ultrastructure. We found that the respiratory response of NAD-ME and PCK type bundle sheath strands to added malate was associated with differences in mitochondrial number, volume, and/or ultrastructure, while NADP-ME type bundle sheath strands did not respond to malate addition. In general, mitochondrial traits reflected the contributions mitochondria make to photosynthesis in the three C types. However, despite the obvious differences in mitochondrial traits, no clear correlation was observed between these traits and R. We suggest that R is primarily driven by cellular maintenance demands and not mitochondrial composition per se, in a manner that is somewhat independent of mitochondrial organic acid cycling in the light.

“A feed-forward Ca2+-dependent mechanism boosting glycolysis and OXPHOS by activating Aralar-malate-aspartate shuttle, upon neuronal stimulation”

SummaryCalcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In cortical neurons using glucose as only fuel, activation by NMDA, which elicits a strong workload dependent on Na+ entry, stimulates glucose uptake, glycolysis, pyruvate and lactate production, and OXPHOS in a Ca2+-dependent way. We find that Ca2+-upregulation of glycolysis, pyruvate levels and respiration, but not glucose uptake, all depend on Aralar/AGC1/Slc25a12, the Ca2+regulated mitochondrial aspartate-glutamate carrier, component of the malate-aspartate shuttle (MAS). Ca2+-activation of MAS increases pyruvate production, which directly fuels workload-stimulated respiration. Also it stimulates glycolysis. MCU silencing had no effect indicating that none of these processes required mitochondrial Ca2+. The neuronal respiratory response to carbachol was also dependent on Aralar, but not on MCU. We also find that cortical neurons are endowed with a constitutive ER-to-mitochondria Ca2+ flow maintaining basal cell bioenergetics in which Ryanodine receptors, RyR2, rather than InsP3R, are responsible for Ca2+ release, and in which MCU does not participate. The results reveal that in neurons using glucose MCU does not participate in OXPHOS regulation under basal or stimulated conditions, while Aralar-MAS appears as the major Ca2+-dependent pathway tuning simultaneously glycolysis and OXPHOS to neuronal activation.