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Mitochondrial mechanism of neuroprotection by CART

Peizhong Mao1, Ardi Ardeshiri, Rachel Jacks

  • 1Department of Public Health & Preventive Medicine, Oregon Health & Science University, Portland, OR 97239-3098, USA.

The European Journal of Neuroscience
|July 20, 2007
PubMed

Insights

The neuropeptide cocaine- and amphetamine-regulated transcript (CART) protects neurons by preserving mitochondrial function. CART enhances succinate dehydrogenase activity and ATP production, crucial for preventing cell death during oxygen-glucose deprivation (OGD).

Area of Science:

  • Neuroscience
  • Mitochondrial Biology
  • Biochemistry

Background:

  • Neuropeptide cocaine- and amphetamine-regulated transcript (CART) exhibits neuroprotective effects against ischemia and oxygen-glucose deprivation (OGD).
  • The precise mechanism underlying CART's neuroprotection and its receptor remain largely uncharacterized.
  • Understanding CART's molecular targets is crucial for elucidating its role in neuronal survival.

Purpose of the Study:

  • To identify the putative receptor for CART and investigate its interaction with mitochondrial proteins.
  • To elucidate the functional consequences of CART binding on mitochondrial activity and cellular energy production.
  • To determine if CART's neuroprotective effects are mediated through the preservation of mitochondrial function.

Main Methods:

  • Yeast two-hybrid screening of a mouse brain cDNA library using CART's carboxy-terminal domain to identify interacting proteins.
  • In vitro pull-down assays to confirm the direct binding between CART and succinate dehydrogenase subunit B (SDHB).
  • Measurement of succinate dehydrogenase (SDH) and Complex II (CII) activity, and ATP production in cultured neurons and isolated mitochondria under basal and OGD conditions.

Main Results:

  • A direct interaction between CART and SDHB was identified and confirmed.
  • Low concentrations of CART (0.2–4 nM) significantly enhanced SDH and CII activity and ATP production in neurons and mitochondria.
  • Pretreatment with CART preserved mitochondrial function, preventing the decline in SDH, CII activity, and ATP levels following OGD.

Conclusions:

  • CART's neuroprotective mechanism is likely linked to its interaction with SDHB, a component of the mitochondrial respiratory chain.
  • CART preserves mitochondrial function and cellular energy production, thereby preventing neuronal death during ischemia-reperfusion injury.
  • These findings highlight CART as a potential therapeutic agent for conditions involving energy failure and neuronal damage.

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