Cell‐Type‐Dependent Metabolic Compensation Preserves Photoreceptor Survival Through Pyruvate Kinase Isoform Balance

Photoreceptors depend on aerobic glycolysis to meet the high biosynthetic demand required for continuous outer segment renewal. Disruption of this metabolic program is increasingly recognized as a contributor to retinal degeneration; however, the coordinated roles of key glycolytic enzymes across retinal cell types remain incompletely understood. Pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA) are central regulators of aerobic glycolysis; however, the mechanisms by which their interplay supports retinal homeostasis remain unclear. Here, we investigated the effects of selectively deleting LDHA alone or in combination with PKM2 in retinal neurons. Rod-specific deletion of LDHA, as well as combined deletion of LDHA and PKM2 in rods, led to progressive photoreceptor degeneration, accompanied by structural disorganization and functional impairment. Loss of LDHA reduced PKM2 expression and induced compensatory upregulation of PKM1; however, PKM1 levels did not reach those of PKM2, correlating with increased susceptibility to degeneration. In contrast, deletion of both LDHA and PKM2 throughout the retina led to robust PKM1 induction to levels comparable to those of PKM2 and was associated with preservation of retinal structure and function. Translating ribosome affinity purification demonstrated that LDHA, LDHB, PKM1, and PKM2 are expressed across multiple retinal cell types, and metabolic analyses revealed that non-rod neurons contribute substantially to retinal lactate production. We propose a PKM isoform balance threshold model in which retinal outcome depends on the level of PKM1 compensation following PKM2 loss. When PKM1 reaches levels comparable to PKM2, retinal structure and function are preserved; insufficient compensation results in degeneration. These findings highlight cell-type-dependent metabolic compensation and pyruvate kinase isoform balance as key determinants of retinal integrity and photoreceptor survival.