| Peroxisomes are single membrane bound organelles participating in a variety of metabolic activities in eukaryotic cells. Their abundance is regulated by a complex interplay of peroxisome synthesis and destruction. Division of pre-existing peroxisomes is the predominant way to synthesize peroxisomes and this process involves the PEX11 proteins, a family of peroxisomal membrane proteins of unknown functions. The goal of my thesis was to analyze the physiological role of PEX11-mediated peroxisome division and to investigate the nature of PEX11's role in the peroxisome division.; To study PEX11 proteins in mammals, we disrupted inducible PEX11α and constitutively expressed PEX11β genes in mice. Mice lacking PEX11β had fewer peroxisomes that were in the elongated, pre-division state, supporting the role of this protein in the peroxisome division. Unexpectly, PEX11β-deficiency resulted in several pathologic features of Zellweger syndrome but did not abrogate peroxisome function demonstrating that pathologies of Zellweger syndrome can occur in the absence of peroxisomal enzyme mislocation This observation challenged the existing models of Zellweger syndrome pathogenesis. PEX11α-deficiency had no significant effect on the peroxisome abundance under normal growth conditions nor did it affect peroxisome proliferation mediated by the Peroxisome Proliferator-Activated Receptorα (PPARα). Instead, PEX11α was required for peroxisome division in response to an atypical peroxisome proliferating agent, 4-phenylbutyrate, which acts independently of PPARα.; We recently identified a third PEX11 gene, PEX11γ, in various species. PEX11γ also encodes a peroxisomal membrane protein, but its overexpression induced peroxisome elongation and clustering, rather than peroxisome proliferation.; We further found that loss of PEX11β affected multiple, unrelated peroxisomal metabolic activities and caused a reduction in peroxisome abundance in the absence of peroxisomal metabolic substrates. Moreover, PEX11 proteins drove peroxisome division independently of peroxisome metabolism in both mammalian cells and yeast These observations suggested that PEX11 proteins play a direct role in peroxisome division. However, PEX11 proteins are not the only factors involved in peroxisome division. Using RNAi technique and dominant negative mutants, we found that DLP1, a dynamin-related protein, plays an essential but transient role in peroxisome division. Furthermore, DLP1 is required for the PEX11-mediated peroxisome division and is recruited to peroxisome membranes during this process. |
