TY - JOUR

T1 - Pharmacological inhibition of mitochondrial soluble adenylyl cyclase in astrocytes causes activation of AMP-activated protein kinase and induces breakdown of glycogen

AU - Jakobsen, Emil

AU - Andersen, Jens V.

AU - Christensen, Sofie K.

AU - Siamka, Olga

AU - Larsen, Martin R.

AU - Waagepetersen, Helle S.

AU - Aldana, Blanca I.

AU - Bak, Lasse K.

N1 - Funding Information: This study was financially supported by the Lundbeck Foundation (EJ; grant no. R249‐2017‐109) and (SKC; grant no. R199‐2015‐1762), the Augustinus Fonden (LKB) and the Hørslev Foundation (LKB). The EPAC‐H188 construct was a kind gift from Kees Jalink, The Netherlands Cancer Institute, Amsterdam (Klarenbeek et al., 2015 ). Funding Information: This study was financially supported by the Lundbeck Foundation (EJ; grant no. R249-2017-109) and (SKC; grant no. R199-2015-1762), the Augustinus Fonden (LKB) and the H?rslev Foundation (LKB). The EPAC-H188 construct was a kind gift from Kees Jalink, The Netherlands Cancer Institute, Amsterdam (Klarenbeek et al.,?2015).

PY - 2021

Y1 - 2021

N2 - Mobilization of astrocyte glycogen is key for processes such as synaptic plasticity and memory formation but the link between neuronal activity and glycogen breakdown is not fully known. Activation of cytosolic soluble adenylyl cyclase (sAC) in astrocytes has been suggested to link neuronal depolarization and glycogen breakdown partly based on experiments employing pharmacological inhibition of sAC. However, several studies have revealed that sAC located within mitochondria is a central regulator of respiration and oxidative phosphorylation. Thus, pharmacological sAC inhibition is likely to affect both cytosolic and mitochondrial sAC and if bioenergetic readouts are studied, the observed effects are likely to stem from inhibition of mitochondrial rather than cytosolic sAC. Here, we report that a pharmacologically induced inhibition of sAC activity lowers mitochondrial respiration, induces phosphorylation of the metabolic master switch AMP-activated protein kinase (AMPK), and decreases glycogen stores in cultured primary murine astrocytes. From these data and our discussion of the literature, mitochondrial sAC emerges as a key regulator of astrocyte bioenergetics. Lastly, we discuss the challenges of investigating the functional and metabolic roles of cytosolic versus mitochondrial sAC in astrocytes employing the currently available pharmacological tool compounds.

AB - Mobilization of astrocyte glycogen is key for processes such as synaptic plasticity and memory formation but the link between neuronal activity and glycogen breakdown is not fully known. Activation of cytosolic soluble adenylyl cyclase (sAC) in astrocytes has been suggested to link neuronal depolarization and glycogen breakdown partly based on experiments employing pharmacological inhibition of sAC. However, several studies have revealed that sAC located within mitochondria is a central regulator of respiration and oxidative phosphorylation. Thus, pharmacological sAC inhibition is likely to affect both cytosolic and mitochondrial sAC and if bioenergetic readouts are studied, the observed effects are likely to stem from inhibition of mitochondrial rather than cytosolic sAC. Here, we report that a pharmacologically induced inhibition of sAC activity lowers mitochondrial respiration, induces phosphorylation of the metabolic master switch AMP-activated protein kinase (AMPK), and decreases glycogen stores in cultured primary murine astrocytes. From these data and our discussion of the literature, mitochondrial sAC emerges as a key regulator of astrocyte bioenergetics. Lastly, we discuss the challenges of investigating the functional and metabolic roles of cytosolic versus mitochondrial sAC in astrocytes employing the currently available pharmacological tool compounds.

KW - AMPK

KW - astrocytes

KW - cAMP

KW - glycogen

KW - mitochondria

KW - soluble adenylyl cyclase (sAC)

U2 - 10.1002/glia.24072

DO - 10.1002/glia.24072

M3 - Journal article

C2 - 34378239

AN - SCOPUS:85112093676

VL - 69

SP - 2828

EP - 2844

JO - GLIA

JF - GLIA

SN - 0894-1491

IS - 12

ER -