Sustained hypoxia modulates mitochondrial DNA content in the neonatal rat brain

Abstract

Effects of placental insufficiency and preterm birth on neurodevelopment can be modeled in experimental settings of neonatal hypoxia in rodents. Here, rat pups were reared in reduced oxygen (9.5%) for eleven days, starting on postnatal day three (P3). This led to a significant reduction in brain and body weight gain in hypoxic pups when compared to age matched normoxia reared controls, plausibly reflecting inability to fulfill energetic needs of normal growth and development. Adaptive processes designed to augment energetic capacity in eukaryotes include stimulation of mitochondrial biogenesis. We show that after eleven days of sustained hypoxia, the levels of nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (Tfam) are elevated and the content of mitochondrial DNA (mtDNA) is greater in the hypoxic P14 pup brain when compared to normoxic conditions. Corresponding immunohistochemical analyses reveal increased density of mtDNA in large cortical neurons. In contrast, no changes in mtDNA content are observed in the brain of pups reared for 24 h (P3-P4) under hypoxic conditions. Together, these data suggest that prolonged inadequate oxygenation may trigger a compensatory increase in neuronal mitochondrial DNA content to partially mitigate compromised energy homeostasis and reduced energetic capacity in the developing hypoxic brain.

Regulation of mitochondrial genome replication by hypoxia: The role of DNA oxidation in D-loop region

“…The effect of hypoxia on mtDNA replication and mitochondrial biogenesis is also complex and may depend on many factors, including sex specificity [57]. Although some cell types respond to hypoxia by reducing their mitochondrial biogenesis and mtDNA content [58–60], mtDNA copy number is reported to increase under hypoxic conditions in many other tissues, including brain, liver, heart, placenta, sperm and blood cells [23–25, 61–67]. Hypoxia, like many other factors that affect mitochondrial biogenesis, utilizes mitochondria-generated ROS as second messengers [68–71].…”

Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity

“…These characteristics seem to be a consequence of decreased oxygen tension. Indeed, hypoxia leads to about 30% loss of mitochondrial density in skeletal muscle 43 , to an increase of mtDNA content 44 , and to generation of ROS 45 to which the reduced anti-oxidant activity might contribute. Interestingly, low-oxygen tension equivalent to hypoxia is prevalent in the muscle stem cell niches 46 as in other stem cell niches (for example, haematopoietic, mesenchymal and neural stem cells) 47 .…”

High fat diet‐induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia

“…HIF‐1α ‐associated increase in liver mtDNA content, is also supported by previous experimental observations on other tissues. For instance, neuronal mitochondrial biogenesis was highly increased after hypoxia or hypoxic–ischemic injury [13, 33].…”

“…Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor involved in cellular and systemic homeostatic response to hypoxia; HIF-1 is a heterodimeric protein complex comprising two subunits, among which, the redox-sensitive HIF-1α is considered to be the major regulator of O 2 -tension-sensitive genes in cells [ 11 ]. Interestingly, HIF-1α has been described as an important regulator of mitochondrial biogenesis in muscle [ 12 ], whereas sustained hypoxia in brain has been associated with an increase in neuronal mtDNA content [ 13 ].…”