PFKM acts as a metabolic switch initiating donut-shaped mitochondrial remodeling to promote osteogenesis

Abstract

Osteogenic differentiation requires sophisticated mitochondrial adaptation to meet bioenergetic demands, yet regulatory checkpoints governing this organelle reorganization remain poorly defined. Through single-cell RNA sequencing reanalysis and metabolic intervention, this study unveils a non-canonical signaling role for PFKM, traditionally recognized solely as a glycolytic enzyme, in orchestrating mitochondrial remodeling during bone formation. Beyond its established metabolic function, Pfkm suppression triggers distinctive donut-shaped mitochondria through a novel signaling cascade. Mechanistically, Pfkm knockdown expands mitochondria-endoplasmic reticulum contacts (MERCs), facilitating mitochondrial calcium influx. Concomitantly, elevated CD38 suppresses protein kinase A (PKA) activity, inducing DRP1 dephosphorylation at Serine 656. This signaling integration promotes DRP1 mitochondrial translocation, driving the characteristic donut architecture. This structural transformation initiates comprehensive mitochondrial quality control (MQC) encompassing enhanced biogenesis, selective mitophagy, and mitochondrial-derived vesicles (MDVs) secretion, collectively optimizing the osteogenic microenvironment and cellular mineralization capacity. In vivo validation demonstrates that AAV-mediated Pfkm knockdown accelerates bone repair in rat calvarial and femoral defect models. This work establishes PFKM as a dual-function regulator bridging metabolism and mitochondrial signaling, offering a potent therapeutic avenue for bone regeneration.

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Funding

National Natural Science Foundation of China (National Science Foundation of China)(82371008)

Scientific Research Projects for Oral Implantology of China Oral Health Foundation (COHF ZZZX202413).

Startup Fund for Scientific Research, Fujian Medical University (Grant No. 2024QH2015)

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