Homeostatic mitophagy scales mitochondrial networks

Abstract Cells scale organelle sizes to ensure physiological function. Here, we uncover a dual role for autophagy in controlling mitochondrial network size with a key function for homeostatic mitophagy. During starvation, non-selective autophagy sustains mitochondrial biogenesis in non-dividing yeast cells resulting in mitochondrial network expansion. Strikingly, Atg32/Bcl2L13-mediated mitophagy scales mitochondria back to pre-starvation size. Without mitophagy, mitochondria size increases two-fold while retaining wildtype-like structural, compositional, and metabolic features. In turn, synthetically elevated mitophagy only mildly reduces mitochondria size, suggesting cells maintain a minimal network size by compensatory biogenesis. Single-cell analysis predicts two metabolically tunable setpoints, mitochondria-to-cell and mitochondria-to-cytosol volume ratios, for mitochondria scaling by autophagy-driven biogenesis and degradation, respectively. Our work reveals how cells use autophagy to scale mitochondria to metabolic and cellular size parameters. One Sentence Summary A homeostatic form of mitophagy controls the network size of mitochondria during starvation.