Shape Matters: The Utility and Analysis of Altered Yeast Mitochondrial Morphology in Health, Disease, and Biotechnology

Abstract

Mitochondria are involved in a wide array of critical cellular processes from energy production to cell death. The morphology (size and shape) of mitochondrial compartments is highly responsive to both intracellular and extracellular conditions, making these organelles highly dynamic. Nutrient levels and stressors both inside and outside the cell inform the balance of mitochondrial fission and fusion and the recycling of mitochondrial components known as mitophagy. The study of mitochondrial morphology and its implications in human disease and microbial engineering have gained significant attention over the past decade. The yeast Saccharomyces cerevisiae offers a valuable model system for studying mitochondria due to its ability to survive without respiring, its genetic tractability, and the high degree of mitochondrial similarity across eukaryotic species. Here, we review how the interplay between mitochondrial fission, fusion, biogenesis, and mitophagy regulates the dynamic nature of mitochondrial networks in both yeast and mammalian systems with an emphasis on yeast as a model organism. Additionally, we examine the crucial role of inter-organelle interactions, particularly between mitochondria and the endoplasmic reticulum, in regulating mitochondrial dynamics. The dysregulation of any of these processes gives rise to abnormal mitochondrial morphologies, which serve as the distinguishing features of numerous diseases, including Parkinson's disease, Alzheimer's disease, and cancer. Notably, yeast models have contributed to revealing the underlying mechanisms driving these human disease states. In addition to furthering our understanding of pathologic processes, aberrant yeast mitochondrial morphologies are of increasing interest to the seemingly distant field of metabolic engineering, following the discovery that compartmentalization of certain biosynthetic pathways within mitochondria can significantly improve chemical production. In this review, we examine the utility of yeast as a model organism to study mitochondrial morphology in both healthy and pathologic states, explore the nascent field of mitochondrial morphology engineering, and discuss the methods available for the quantification and classification of these key mitochondrial morphologies.

Keywords: analysis; biofuel; cancer; contact sites; engineering; fission; fusion; imaging; mitochondria; morphology; neurodegenerative; pathology.

Figure 1

Mitochondrial morphology is the result of a balance between fission and fusion processes and responds to the cell’s metabolic state.

Figure 2

Yeast mitochondrial fusion. (A) Fzo1p homodimerizes on the OMM and associates with other Fzo1p homodimers on neighboring mitochondria, tethering the two mitochondrial compartments together. Meanwhile, Ugo1p acts as a bridge between on Fzo1p and Mgm1p assemblies in the OMM and IMM, respectively, to coordinate the outer and inner mitochondrial membrane fusion machinery. (B) Following fusion of the OMM, Mgm1p catalyzes the fusion of the IMM. (C) Hydrolysis of GTP by Fzo1p induces a conformational change in these homodimeric complexes that allows for Fzo1p ubiquitylation by the F-box protein Mdm30p, ultimately leading to Fzo1 degradation and clearance, which maintains steady-state levels of Fzo1p.

Figure 3

Yeast mitochondrial fission. (A) Dnm1p is recruited to the surface of the mitochondria by Fis1p, which is anchored to the OMM, through adapter proteins such as Mdv1p. (B) On the surface, Dnm1p collects and self-assembles into ring-like structures around the mitochondrial tubule, leading to (C) constriction and the formation of a site for scission.