Fig. 2: 4-HMA supplementation improves cerebellar histology in Hpdl^−/− mice.

a, Representative electron micrographs of the cerebella of P11 Hpdl^+/+, Hpdl^+/− and Hpdl^−/− mouse pups reveal substantial changes in cerebellar mitochondrial morphology. The mitochondria (marked by arrowheads) in Hpdl^+/+ and Hpdl^+/− mouse pups are intact, whereas those in the cerebella of Hpdl^−/− mouse pups are fragmented. Supplementing Hpdl^−/− mice with 10 mg kg⁻¹ 4-HMA starting on P2–3 (Hpdl^−/− + 4-HMA) restores cerebellar mitochondrial ultrastructure. Dashed boxes indicate area of interest highlighted in the second row. Scale bars, 1 μm. b, Quantification of mitochondrial perimeter in electron micrographs of the cerebella of P11 Hpdl^+/+, Hpdl^+/− and Hpdl^−/− mouse pups as well as P11 Hpdl^−/− mouse pups treated with 4-HMA. Mitochondria in the Hpdl^−/− mouse pups are smaller than those of the Hpdl^+/+ and Hpdl^+/− pups. 4-HMA treatment increases the size of the mitochondria in the Hpdl^−/− pups, although not to the same size of mitochondria in Hpdl^+/+ pups. n = 117 (Hpdl^+/+), 227 (Hpdl^+/−), 677 (Hpdl^−/−) and 258 (Hpdl^−/− + 4-HMA). c, P11 Hpdl^−/− pups have marked cerebellar atrophy with PCs (arrowheads) showing vacuolization and intracellular oedema, thinning of the inner granular layer (IGL) and molecular layer and compaction of the external granular layer (EGL). These abnormalities are improved to near-wild-type morphology by supplementation with 4-HMA starting on P2–3 (Hpdl^−/− + 4-HMA). Dashed boxes indicate area of interest highlighted in the next row. Scale bars, 500 μm (top row); 125 μm (middle row); 62.5 μm (bottom row). Raw data and means are shown. P values are indicated on each plot. P values > 0.05 are not shown. For b, significance was tested by two-way ANOVA followed by Tukey’s post hoc test.

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