Mitochondria Take the Lead: How Metabolism Rewrites Cell Fate
A study led by Scott W. Lowe (Nature, 2025) brings mitochondria into the spotlight — not just as power generators, but as active decision-makers in stem cell fate.
At the heart of the discovery is OGDH, a key enzyme in the mitochondrial TCA cycle. Traditionally seen as a simple metabolic actor, OGDH is now revealed as a master regulator of cell identity in the intestinal epithelium.
- In absorptive cells, high OGDH activity supports energy production and biosynthesis through oxidative phosphorylation, driving cell growth.
- In contrast, low OGDH levels in secretory cells cause an accumulation of α-ketoglutarate (αKG) — a metabolite that acts as a signaling molecule, inducing epigenetic reprogramming and pushing cells toward differentiation.
Using inducible OGDH knockdown in mice, 3D organoid cultures, metabolic tracing, and transcriptomics, the researchers demonstrated that modulating αKG levels can shift stem cell
