Regulation of Heme Oxygenase and Its Cross-Talks with Apoptosis and Autophagy under Different Conditions in Drosophila

Abstract

Heme oxygenase (HO) is one of the cytoprotective enzymes that can mitigate the effects of oxidative stress. Here, we found that the ho mRNA level oscillates in the brain of Drosophila melanogaster with two minima at the beginning of the day and night. This rhythm was partly masked by light as its pattern changed in constant darkness (DD). It followed a similar trend in the clock mutant per01 under light/dark regime (LD12:12); however, differences between time points were not statistically significant. In older flies (20 days old), the rhythm was vanished; however, 15 days of curcumin feeding restored this rhythm with an elevated ho mRNA level at all time points studied. In addition, flies exposed to paraquat had higher ho expression in the brain, but only at a specific time of the day which can be a protective response of the brain against stress. These findings suggest that the expression of ho in the fly’s brain is regulated by the circadian clock, light, age, exposure to stress, and the presence of exogenous antioxidants. We also found that HO cross-talks with apoptosis and autophagy under different conditions. Induction of neuronal ho was accompanied by increased transcription of apoptosis and autophagy-related genes. However, this trend changed after exposure to curcumin and paraquat. Our results suggest that HO is involved in the control of apoptotic and autophagic key processes protecting the brain against oxidative damage.

Sexual deprivation induces a CRF independent stress response and decreases resistance to stressors inDrosophilavia a subpopulation of Neuropeptide F receptor-expressing neurons

“…HO is a rate-limiting enzyme that degrades heme into biliverdin, carbon monoxide (CO), and iron 125 . In Drosophila, ho gene is expressed in different brain tissues including the optic lobe, the central brain, and glial cells, and plays an important role in cell survival and protection against paraquat-induced oxidative stress 126 . This is consistent with rejected males experiencing oxidative stress and are thus more sensitive to paraquat.…”

The dual role of heme oxygenase in regulating apoptosis in the nervous system of Drosophila melanogaster

“…The experiments with curcumin as an antioxidant and a compound affecting HO and apoptosis revealed interactions between HO signaling pathway and apoptosis. It has already been reported in both mammals (McNally et al, 2007;Lima et al, 2011;Cremers et al, 2014;Masuelli et al, 2017;Yang et al, 2017;Peng et al, 2018;Zhang et al, 2018;Zhong et al, 2018) and flies (Abaquita et al, 2021). Curcumin activates the nuclear factor erythroid 2-like 2 (Nrf2) pathway that regulates ho expression (Peng et al, 2018;Zhong et al, 2018).…”

“…Elevated ho mRNA level by pro- or anti-oxidative compounds is accompanied by changes in the expression pattern of genes involved in autophagy (degradation and recycling process) and apoptosis (elimination of damaged cells). Moreover, increasing or decreasing ho expression in neurons affects the transcript levels of these genes ( Abaquita et al, 2021 ).…”

“…The antioxidative role of HO is based on scavenging of free radical species, particularly in the brain and rest of the nervous system in both mammals and D. melanogaster ( Loboda et al, 2008 ; Abaquita et al, 2021 ). The energy-demanding synaptic transmission ( Harris et al, 2012 ) is usually associated with the overproduction of reactive oxygen and nitrogen species (e.g.…”

“…Then, we employed different conditions (i.e. different ho expression levels and aging) to further investigate how neuronal HO affects the regulation of apoptosis and autophagy, which we assumed to be two of the many mechanisms that are regulated by ho expression levels in the Drosophila brain ( Damulewicz et al, 2019 ; Abaquita et al, 2021 ). We targeted the expression of ho in two specific cell types (i.e.…”